BioPAX pathway converted from "Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways" in the Reactome database. Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> NOD1/2 Signaling Pathway NOD1/2 Signaling Pathway This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> iE-DAP elicits a NOD1 response iE-DAP elicits a NOD1 response This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 622271 1 cytosol GO 0005829 gamma-D-glutamyl-meso-diaminopimelic acid [ChEBI:59271] gamma-D-glutamyl-meso-diaminopimelic acid Reactome http://www.reactome.org ChEBI 59271 Reactome DB_ID: 9764147 1 UniProt:Q8BHB0 Nod1 Mus musculus NCBI Taxonomy 10090 UniProt Q8BHB0 Chain Coordinates 1 EQUAL 953 EQUAL Reactome DB_ID: 9764149 1 NOD1:iE-DAP [cytosol] NOD1:iE-DAP Reactome DB_ID: 622271 1 Reactome DB_ID: 9764147 1 1 EQUAL 953 EQUAL Reactome Database ID Release 78 9764149 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764149 Reactome R-MMU-168408 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-168408.1 Reactome Database ID Release 78 9764187 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764187 Reactome R-MMU-168400 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-168400.1 Early studies suggested that NOD1 and NOD2 responded to lipopolysaccharides (LPS), but this was later shown to be due to contamination of LPS with bacterial peptidoglycans (PGNs), the true elicitor for NODs. It is generally believed that PGNs bind NOD1 though this remains to be formally demonstrated. NOD1 senses PGN moieties with a minimal dipeptide structure of D-gamma-glutamyl-meso-diaminopimelic acid (iE-DAP), which is unique to PGN structures from all Gram-negative bacteria and certain Gram-positive bacteria, including the genus Listeria and Bacillus. Attachment of acyl residues enhances NOD1 stimulation several hundred fold, possibly by facilitating PGN entry into the cell (Hasegawa et al. 2007). 12796777 Pubmed 2003 An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid Chamaillard, M Hashimoto, M Horie, Y Masumoto, J Qiu, S Saab, L Ogura, Y Kawasaki, A Fukase, K Kusumoto, S Valvano, MA Foster, SJ Mak, TW Nunez, G Inohara, N Nat Immunol 4:702-7 17322292 Pubmed 2007 A role of lipophilic peptidoglycan-related molecules in induction of Nod1-mediated immune responses Hasegawa, M Kawasaki, A Yang, K Fujimoto, Y Masumoto, J Breukink, E Nunez, G Fukase, K Inohara, N J Biol Chem 282:11757-64 12791997 Pubmed 2003 Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan Girardin, SE Boneca, IG Carneiro, LA Antignac, A Jéhanno, M Viala, J Tedin, K Taha, MK Labigne, A Zähringer, U Coyle, AJ DiStefano, PS Bertin, J Sansonetti, PJ Philpott, DJ Science 300:1584-7 inferred by electronic annotation IEA GO IEA MDP elicits a NOD2 response MDP elicits a NOD2 response This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764154 1 UniProt:Q8K3Z0 Nod2 Nod2 Card15 Nod2 FUNCTION Involved in gastrointestinal immunity. Upon stimulation by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, binds the proximal adapter receptor-interacting RIPK2, which recruits ubiquitin ligases as XIAP, BIRC2, BIRC3, INAVA and the LUBAC complex, triggering activation of MAP kinases and activation of NF-kappa-B signaling. This in turn leads to the transcriptional activation of hundreds of genes involved in immune response (PubMed:22607974). Required for MDP-induced NLRP1-dependent CASP1 activation and IL1B release in macrophages (PubMed:18511561). Component of an autophagy-mediated antibacterial pathway together with ATG16L1. Plays also a role in sensing single-stranded RNA (ssRNA) from viruses. Interacts with mitochondrial antiviral signaling/MAVS, leading to activation of interferon regulatory factor-3/IRF3 and expression of type I interferon.SUBUNIT Component of a signaling complex consisting of ARHGEF2, NOD2 and RIPK2. Interacts (via CARD domain) with RIPK2 (via CARD domain). Interacts with ATG16L1. Interacts (via NACHT domain) with CARD9 (PubMed:17187069). Interacts with ANKRD17 (via N-terminus). Interacts with HSPA1A; the interaction enhances NOD2 stability. Interacts (via both CARD domains) with HSP90; the interaction enhances NOD2 stability (PubMed:23019338). Interacts (via CARD domain) with SOCS3; the interaction promotes NOD2 degradation. Interacts (via CARD domain) with ERBBI2P; the interaction inhibits activation of NOD2 (PubMed:16203728). Interacts (via CARD domain) with CASP1; this interaction leads to IL1B processing (PubMed:18511561). Also interacts with CASP4. Interacts with NLRP1; this interaction is enhanced in the presence of muramyl dipeptide (MDP) and leads to increased IL1B release. Interacts with MAPKBP1; the interaction is enhanced in the presence of muramyl dipeptide (MDP). Interacts with INAVA; the interaction takes place upon PRR stimulation. Interacts with ANKHD1, C10ORF67, CHMP5, DOCK7, ENTR1, KRT15, LDOC1, PPP1R12C, PPP2R3B, TRIM41 and VIM (By similarity). Interacts with NLRP12; this interaction promotes degradation of NOD2 through the ubiquitin-proteasome pathway (By similarity).DOMAIN The ATG16L1-binding motif mediates interaction with ATG16L1.DOMAIN Intramolecular interactions between the N-terminal moiety and the leucine-rich repeats (LRR) may be important for autoinhibition in the absence of activating signal. In the absence of LRRs, the protein becomes a constitutive activator of CASP1 cleavage and proIL1B processing.PTM Polyubiquitinated following MDP stimulation, leading to proteasome-mediated degradation. UniProt Q8K3Z0 1 EQUAL 1040 EQUAL Reactome DB_ID: 708341 1 muramyl dipeptide [ChEBI:59414] muramyl dipeptide ChEBI 59414 Reactome DB_ID: 9764156 1 MDP:NOD2 [cytosol] MDP:NOD2 Reactome DB_ID: 9764154 1 1 EQUAL 1040 EQUAL Reactome DB_ID: 708341 1 Reactome Database ID Release 78 9764156 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764156 Reactome R-MMU-168414 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-168414.1 Reactome Database ID Release 78 9764195 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764195 Reactome R-MMU-168412 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-168412.1 Muramyl dipeptide (MDP) is an essential structural component of bacterial peptidoglycan (PGN) and the minimal elicitor recognized by NOD2. As MDP is present in nearly all bacteria NOD2 is a general sensor of bacteria. NOD2 has additionally been reported to respond to ssRNA (Sabbah et al. 2009) and play a role in T cell activation (Shaw et al. 2011). 12527755 Pubmed 2003 Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection Girardin, SE Boneca, IG Viala, J Chamaillard, M Labigne, A Thomas, G Philpott, DJ Sansonetti, PJ J Biol Chem 278:8869-72 19701189 Pubmed 2009 Activation of innate immune antiviral responses by Nod2 Sabbah, A Chang, TH Harnack, R Frohlich, V Tominaga, K Dube, PH Xiang, Y Bose, S Nat Immunol 10:1073-80 12514169 Pubmed 2003 Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease Inohara, N Ogura, Y Fontalba, A Gutierrez, O Pons, F Crespo, J Fukase, K Inamura, S Kusumoto, S Hashimoto, M Foster, SJ Moran, AP Fernandez-Luna, JL Nunez, G J Biol Chem 278:5509-12 21251876 Pubmed 2011 The ever-expanding function of NOD2: autophagy, viral recognition, and T cell activation Shaw, MH Kamada, N Warner, N Kim, YG Nunez, G Trends Immunol 32:73-9 inferred by electronic annotation IEA GO IEA Activated NOD1 oligomerizes Activated NOD1 oligomerizes This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764149 6 Reactome DB_ID: 9764151 1 NOD1:iE-DAP oligomer [cytosol] NOD1:iE-DAP oligomer Reactome DB_ID: 9764149 6 Reactome Database ID Release 78 9764151 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764151 Reactome R-MMU-622306 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-622306.1 Reactome Database ID Release 78 9787247 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787247 Reactome R-MMU-622310 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-622310.1 NOD1 is activated by iE-DAP in a LRR domain dependent manner. The LRR domain has a negative influence on NOD1 self-association (Inohara et al. 2000); binding of iE-DAP likely causes conformational changes that free the NACHT domain, allowing oligomerization and subsequent association of other proteins. Coimmunoprecipitation experiments demonstrate that NOD1 can interact with itself (Inohara et al. 1999) via the NACHT domain (Inohara et al. 2000). NACHT domains are part of the AAA+ domain family. Members of this family form hexamers or heptamers. Based on this observation, NOD1 and NOD2 are believed to form oligomers of this size (Martinon & Tschopp, 2005). 15967716 Pubmed 2005 NLRs join TLRs as innate sensors of pathogens Martinon, F Tschopp, Jürg Trends Immunol 26:447-54 10880512 Pubmed 2000 An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways Inohara, N Koseki, T Lin, J del Peso, L Lucas, PC Chen, FF Ogura, Y Nunez, G J Biol Chem 275:27823-31 10329646 Pubmed 1999 Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB Inohara, N Koseki, T del Peso, L Hu, Y Yee, C Chen, S Carrio, R Merino, J Liu, D Ni, J Nunez, G J Biol Chem 274:14560-7 inferred by electronic annotation IEA GO IEA Activated NOD2 oligomerizes Activated NOD2 oligomerizes This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764156 6 Reactome DB_ID: 9764158 1 MDP:NOD2 oligomer [cytosol] MDP:NOD2 oligomer Reactome DB_ID: 9764156 6 Reactome Database ID Release 78 9764158 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764158 Reactome R-MMU-708350 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-708350.1 Reactome Database ID Release 78 9787395 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787395 Reactome R-MMU-708349 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-708349.1 NOD2 is activated by MDP in a LRR domain dependent manner. Based on studies of NOD1 activation and structural data from the NLR-related scaffold Apaf-1, the LRR domain is believed to have a negative influence on NOD2 self-association (Inohara et al. 2000, Riedl & Salvesen 2007); binding of MDP is believed to cause conformational changes that free the NACHT domain, allowing oligomerization and subsequent association of other proteins. Coimmunoprecipitation experiments demonstrate that NOD1 can interact with itself (Inohara et al. 1999) via the NACHT domain (Inohara et al. 2000). NACHT domains are part of the AAA+ domain family. Members of this family form hexamers or heptamers. Based on these observations, NOD2 is generally believed to form hexamers or heptamers (Martinon & Tschopp, 2005). NOD2 oliogomerization has been observed in NOD2-transfected HEK293T cells (Zhao et al. 2007). 17377525 Pubmed 2007 The apoptosome: signalling platform of cell death Riedl, SJ Salvesen, Guy S. Nat Rev Mol Cell Biol 8:405-13 17303577 Pubmed 2007 Differential modulation of Nods signaling pathways by fatty acids in human colonic epithelial HCT116 cells Zhao, L Kwon, MJ Huang, S Lee, JY Fukase, K Inohara, N Hwang, DH J Biol Chem 282:11618-28 inferred by electronic annotation IEA GO IEA Activated NOD oligomer recruites RIP2 (RICK) Activated NOD oligomer recruites RIP2 (RICK) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9764160 1 PAMP:NOD oligomer [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 9764189 6 UniProt:P58801 Ripk2 Ripk2 Ripk2 FUNCTION Serine/threonine/tyrosine kinase that plays an essential role in modulation of innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD domains. Once recruited, autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3. The polyubiquitinated protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is release from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Plays also a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation. Plays a role in the inactivation of RHOA in response to NGFR signaling (PubMed:26646181).SUBUNIT Found in a signaling complex consisting of at least ARHGEF2, NOD2 and RIPK2. Interacts with ARHGEF2; the interaction mediates tyrosine phosphorylation of RIPK2 by Src kinase CSK. Binds to CFLAR/CLARP and CASP1 via their CARD domains. Binds to BIRC3/c-IAP1 and BIRC2/c-IAP2, TRAF1, TRAF2, TRAF5 and TRAF6. May be a component of both the TNFRSF1A and TNRFSF5/CD40 receptor complex. Interacts with NOD1. Interacts (via CARD domain) with NOD2 (via CARD domain). Interacts with MAP3K4; this interaction sequesters RIPK2 from the NOD2 signaling pathway. Interacts with IKBKG/NEMO. The polyubiquitinated protein interacts with MAP3K7/TAK1. Interacts with XIAP/BIRC4. Interacts with NLRP10 (By similarity). Interacts with CARD9 (PubMed:17187069). Interacts with INAVA; the interaction takes place upon PRR stimulation. Interacts (via CARD domain) with NGFR (via death domain) (By similarity).DOMAIN Contains an N-terminal kinase domain and a C-terminal caspase activation and recruitment domain (CARD) that mediates the recruitment of CARD-containing proteins.PTM Autophosphorylated. Autophosphorylation at Tyr-473 is necessary for effective NOD2 signaling.PTM Ubiquitinated on Lys-209; undergoes 'Lys-63'-linked polyubiquitination catalyzed by ITCH. Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B. Also undergoes 'Met-1'-linked polyubiquitination; the head-to-tail linear polyubiquitination is mediated by the LUBAC complex in response to NOD2 stimulation. Linear polyubiquitination is restricted by FAM105B/otulin, probably to limit NOD2-dependent proinflammatory signaling activation of NF-kappa-B (By similarity). Undergoes 'Lys-63'-linked deubiquitination by MYSM1 to attenuate NOD2-mediated inflammation and tissue damage (PubMed:30405132).DISRUPTION PHENOTYPE Mice show a lack of chemokine production induced by bacterial peptidoglycans. RIPK2 deficiency affects cellular signaling and cytokine responses triggered by NOD1 and NOD2 ligands, but not TLR ligands.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. UniProt P58801 1 EQUAL 540 EQUAL Reactome DB_ID: 9764191 1 PAMP:NOD oligomer:RIP2 [cytosol] PAMP:NOD oligomer:RIP2 Converted from EntitySet in Reactome Reactome DB_ID: 9764160 1 Reactome DB_ID: 9764189 6 1 EQUAL 540 EQUAL Reactome Database ID Release 78 9764191 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764191 Reactome R-MMU-168409 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-168409.1 Reactome Database ID Release 78 9764193 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764193 Reactome R-MMU-168405 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-168405.1 NOD1 and NOD2 (NOD) interact with the inflammatory kinase RIP2 (RICK) via a homophilic association between CARD domains (Inohara et al. 1999, Ogura et al. 2001). This has the effect of bringing several RIP2 molecules into close proximity, enhancing RIP2-RIP2 interactions (Inohara et al. 2000), a key step in what is termed the 'Induced Proximity Model' for NOD activation of NFkappaB. Note that though the interaction of every NOD with RIP2 is implied here this may not be required for RIP2 activation. RIP2 recruitment leads to subsequent activation of NFkappaB. The kinase activity of RIP2 was initially described as not required (Inohara et al. 2000) but subsequently suggested to be involved in determining signal strength (Windheim et al. 2007) and recently found to be essential for maintaining RIP2 stability and it's role in mediating NOD signaling (Nembrini et al. 2009). 19473975 Pubmed 2009 The kinase activity of Rip2 determines its stability and consequently Nod1- and Nod2-mediated immune responses Nembrini, C Kisielow, J Shamshiev, AT Tortola, L Coyle, AJ Kopf, M Marsland, BJ J Biol Chem 284:19183-8 17348859 Pubmed 2007 Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide Windheim, M Lang, C Peggie, M Plater, LA Cohen, P Biochem J 404:179-90 10224040 Pubmed 1999 Human CARD4 protein is a novel CED-4/Apaf-1 cell death family member that activates NF-kappaB Bertin, J Nir, WJ Fischer, CM Tayber, OV Errada, PR Grant, JR Keilty, JJ Gosselin, ML Robison, KE Wong, GH Glucksmann, MA DiStefano, PS J Biol Chem 274:12955-8 11087742 Pubmed 2001 Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB Ogura, Y Inohara, N Benito, A Chen, FF Yamaoka, S Nunez, G J Biol Chem 276:4812-8 inferred by electronic annotation IEA GO IEA RIP2 binds NEMO RIP2 binds NEMO This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9763953 1 UniProt:O88522 Ikbkg UniProt O88522 1 EQUAL 419 EQUAL Reactome DB_ID: 9764191 1 Reactome DB_ID: 9787333 1 PAMP:NOD oligomer:RIP2:NEMO [cytosol] PAMP:NOD oligomer:RIP2:NEMO Reactome DB_ID: 9763953 1 1 EQUAL 419 EQUAL Reactome DB_ID: 9764191 1 Reactome Database ID Release 78 9787333 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787333 Reactome R-MMU-688994 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-688994.1 Reactome Database ID Release 78 9787335 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787335 Reactome R-MMU-622415 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-622415.1 An intermediate region located between the CARD and kinase domains mediates the interaction of RIP2 with the IKK complex regulatory subunit NEMO. This interaction is presumed to link NOD1:RIP2 to the IKK complex, ultimately leading to the phosphorylation of IkappaB-alpha and the activation of NF-kappaB (Inohara et al. 2000). Although every NOD molecule in the oligomeric complex is represented as binding RIP2, binding to every member of the complex may not be required for subsequent signaling events. 18079694 Pubmed 2008 A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation Hasegawa, M Fujimoto, Y Lucas, PC Nakano, H Fukase, K Nunez, G Inohara, N EMBO J 27:373-83 inferred by electronic annotation IEA GO IEA 6.3.2.19 RIP2 induces K63-linked ubiquitination of NEMO RIP2 induces K63-linked ubiquitination of NEMO This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764139 1 K63polyUb [cytosol] K63polyUb Reactome DB_ID: 9787333 1 Reactome DB_ID: 9787444 1 PAMP:NOD oligomer:RIP2:K63-pUb-K285-NEMO [cytosol] PAMP:NOD oligomer:RIP2:K63-pUb-K285-NEMO Reactome DB_ID: 9764139 1 Reactome DB_ID: 9787442 1 PAMP:NOD oligomer:RIP2:K63-Ub-K285-NEMO [cytosol] PAMP:NOD oligomer:RIP2:K63-Ub-K285-NEMO Reactome DB_ID: 9764191 1 Reactome DB_ID: 9787440 1 ubiquitinylated lysine at 285 (in Homo sapiens) 285 EQUAL ubiquitinylated lysine [MOD:01148] 1 EQUAL 419 EQUAL Reactome Database ID Release 78 9787442 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787442 Reactome R-MMU-741389 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-741389.1 Reactome Database ID Release 78 9787444 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787444 Reactome R-MMU-741418 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-741418.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9764236 TRAF6 E3/E2 ubiquitin ligase complex [cytosol] TRAF6 E3/E2 ubiquitin ligase complex Reactome DB_ID: 9764075 1 UBE2N:UBE2V1 [cytosol] UBE2N:UBE2V1 Reactome DB_ID: 9764069 1 UniProt:P61089 Ube2n UniProt P61089 1 EQUAL 152 EQUAL Reactome DB_ID: 9764073 1 UniProt:Q9CZY3 Ube2v1 UniProt Q9CZY3 2 EQUAL 147 EQUAL Reactome Database ID Release 78 9764075 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764075 Reactome R-MMU-202463 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-202463.1 Reactome DB_ID: 9763826 1 UniProt:P70196-1 Traf6 Traf6 Traf6 FUNCTION E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as IKBKG, IRAK1, AKT1 and AKT2. Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation (By similarity). Leads to the activation of NF-kappa-B and JUN. May be essential for the formation of functional osteoclasts. Seems to also play a role in dendritic cells (DCs) maturation and/or activation. Represses c-Myb-mediated transactivation, in B-lymphocytes. Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor. Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation. Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homotrimer (By similarity). Homooligomer (By similarity). N-terminal region is dimeric while C-terminal region is trimeric; maybe providing a mode of oligomerization. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and MYD88; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK (By similarity). Associates with NGFR, TNFRSF17, IRAK2, IRAK3, PELI2, PELI3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TDP2. Binds UBE2V1. Interacts with MAVS/IPS1. Interacts with TAX1BP1 (By similarity). Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ. Interacts with IL1RL1. Interacts with AJUBA (By similarity). Interacts with TRAFD1. Interacts with TICAM2. Interacts with ZFAND5. Interacts with ARRB1 and ARRB2 (By similarity). Interacts with MAP3K7 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3. Interacts (via TRAF domains) with NUMBL (via C-terminal) (By similarity). Interacts (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with RBCK1 (By similarity). Interacts with LIMD1 (via LIM domains). Interacts with RSAD2/viperin. Interacts with IFIT3 (via N-terminus) (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain). Interacts with CARD14 (By similarity). Interacts with CD40 and MAP3K8; the interaction is required for ERK activation. Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (By similarity). Interacts with TANK; this interaction increases in response to DNA damage (By similarity). Interacts with USP10; this interaction increases in response to DNA damage (By similarity). Interacts with ZC3H12A; this interaction increases in response to DNA damage and is stimulated by TANK (By similarity). Interacts with WDFY3 (PubMed:27330028). Interacts with TRIM13 (By similarity). Interacts with GPS2 (PubMed:22424771). Interacts (via C-terminus) with SASH1 (By similarity). Interacts with LRRC19 (By similarity). Interacts with IL17RA AND TRAF3IP2. Interacts with TOMM70 (By similarity).TISSUE SPECIFICITY Highly expressed in brain, lung, liver, skeletal muscle, and kidney; lower expression in heart, spleen, and testis.DOMAIN The coiled coil domain mediates homo- and hetero-oligomerization.DOMAIN The MATH/TRAF domain binds to receptor cytoplasmic domains.PTM Sumoylated on Lys-124, Lys-142 and Lys-461 with SUMO1.PTM Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation with IL17A (By similarity). Polyubiquitinated; after cell stimulation with IL1B or TGFB. This ligand-induced cell stimulation leads to dimerization/oligomerization of TRAF6 molecules, followed by auto-ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6 activation. This 'Lys-63' site-specific poly-ubiquitination appears to be associated with the activation of signaling molecules. Endogenous autoubiquitination occurs only for the cytoplasmic form. Deubiquitinated by USP10 in a TANK-dependent manner, leading to the negative regulation of NF-kappa-B signaling upon DNA damage. LRRC19 induces 'Lys-63' ubiquitination (PubMed:25026888).DISRUPTION PHENOTYPE Abrogation of IL-1-induced activation of NF-kappa-B, MAPK8/JNK and MAPK14/p38. Animals appear normal at birth but become smaller after one week. Show runting, failure of tooth eruption and die after three weeks. Exhibit severe osteopetrosis, thymic atrophy, lymph node deficiency, splenomegaly, and have alopecia and lack sweat glands.SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily. UniProt P70196-1 1 EQUAL 522 EQUAL Reactome Database ID Release 78 9764236 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764236 Reactome R-MMU-1248657 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-1248657.1 GO 0004842 GO molecular function Reactome Database ID Release 78 9787445 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787445 Reactome Database ID Release 78 9787447 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787447 Reactome R-MMU-741386 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-741386.1 RIP2 induces the K63-linked ubiquitination of NEMO at K285 and K399, positively modulating subsequent NF-kappaB activation (Abbot et al. 2007). TRAF6 E3 ligase is capable of performing this ubiquitination step when overexpressed in HEK239 cells, and this effect is blocked if RIP2 siRNA is co-transfected, but small interfering RNA (siRNA) experiments indicate that there are additional E3 ligases that can substitute for TRAF6 in NEMO ubiquitination. In addition to TRAF6, the K63-specific E2 ligase Ubc13 is required for NEMO ubiquitination suggesting a common mechanism for NEMO ubiquitination in NOD and TLR signaling. 17562858 Pubmed 2007 Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains Abbott, Derek W Yang, Y Hutti, JE Madhavarapu, S Kelliher, MA Cantley, Lewis C Mol Cell Biol 27:6012-25 inferred by electronic annotation IEA GO IEA CYLD deubiquitinates NEMO CYLD deubiquitinates NEMO This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9787444 1 Reactome DB_ID: 9764139 1 Reactome DB_ID: 9787333 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9760438 UniProt:Q80TQ2 Cyld UniProt Q80TQ2 1 EQUAL 956 EQUAL GO 0061578 GO molecular function Reactome Database ID Release 78 9787448 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787448 Reactome Database ID Release 78 9787450 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787450 Reactome R-MMU-741411 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-741411.1 RIP2-induced ubiquitination of NEMO and consequent NFkappaB activation can be reversed in a dose-responsive manner by the deubiquitinase CYLD, suggesting that CYLD negatively regulates RIP2-induced NEMO ubiquitinylation. 15620648 Pubmed 2004 The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO Abbott, Derek W Wilkins, A Asara, JM Cantley, Lewis C Curr Biol 14:2217-27 12917691 Pubmed 2003 The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination Kovalenko, A Chable-Bessia, C Cantarella, G Israel, A Wallach, D Courtois, G Nature 424:801-5 inferred by electronic annotation IEA GO IEA RIP2 is K63 polyubiquitinated RIP2 is K63 polyubiquitinated This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764139 6 Reactome DB_ID: 9787333 1 Reactome DB_ID: 9764164 1 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO [cytosol] PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO Reactome DB_ID: 9763953 1 1 EQUAL 419 EQUAL Reactome DB_ID: 9764139 6 Reactome DB_ID: 9764162 1 PAMP:NOD oligomer:K63-Ub-RIP2 [cytosol] PAMP:NOD oligomer:K63-Ub-RIP2 Reactome DB_ID: 9764143 6 ubiquitinylated lysine at 209 (in Homo sapiens) 209 EQUAL 1 EQUAL 540 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9764160 1 Reactome Database ID Release 78 9764162 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764162 Reactome R-MMU-706482 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-706482.1 Reactome Database ID Release 78 9764164 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764164 Reactome R-MMU-706480 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-706480.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9787378 RIP2 ubiquitin ligases [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Itch [cytosol] UniProt Q8C863 GO 0019787 GO molecular function Reactome Database ID Release 78 9787379 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787379 Reactome Database ID Release 78 9787381 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787381 Reactome R-MMU-688137 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-688137.1 The close physical proximity of RIP2 proteins that results from NOD oligomerization triggers the conjugation of lysine (K)-63 linked polyubiquitin chains onto RIP2. Ubiquitination at K209 within the kinase domain was required for subsequent NFkappaB signaling (Hasegawa et al. 2008). The identity of the ubiquitin ligase responsible is an open question, with several candidates capable of RIP2 ubiquitination. TRAF6 has been reported as the ubiquitin ligase responsible (Yang et al. 2007) but subsequent reports suggest it is not responsible (see Tao et al. 2009 and Bertrand et al. 2009). Other candidates include the HECT-domain containing E3 ubiquitin ligase ITCH, which is able to K63 ubiquitinate RIP2 (at an undetermined site that is not K209) and is required for optimal NOD2:RIP2-induced p38 and JNK activation, while inhibiting NOD2:RIP2-induced NFkappaB activation (Tao et al. 2009). The Baculoviral IAP repeat-containing proteins (Birc/cIAP) 2 and 3 have also been shown capable of RIP2 ubiquitination and required for NOD2 signaling (Bertrand et al. 2009). It has been suggested that ITCH and a K209 E3 ligase compete for ubiquitination of RIP2, so that a subset of RIP2 becomes ubiquitinated on K209 to stimulate NEMO ubiquitination and subsequent NFkappaB activation while a second subset of RIP2 is polyubiquitinated by ITCH to activate JNK and p38 signaling (Tao et al. 2009). 19464198 Pubmed 2009 Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2 Bertrand, MJ Doiron, K Labbé, K Korneluk, RG Barker, PA Saleh, M Immunity 30:789-801 19592251 Pubmed 2009 ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways Tao, M Scacheri, PC Marinis, JM Harhaj, EW Matesic, LE Abbott, Derek W Curr Biol 19:1255-63 17947236 Pubmed 2007 NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2 Yang, Y Yin, C Pandey, A Abbott, Derek W Sassetti, C Kelliher, MA J Biol Chem 282:36223-9 inferred by electronic annotation IEA GO IEA TNFAIP3 (A20) deubiquitinates RIP2 TNFAIP3 (A20) deubiquitinates RIP2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764164 1 Reactome DB_ID: 9764139 6 Reactome DB_ID: 9787333 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9760442 UniProt:Q60769 Tnfaip3 UniProt Q60769 1 EQUAL 790 EQUAL Reactome Database ID Release 78 9787371 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787371 Reactome Database ID Release 78 9787373 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787373 Reactome R-MMU-688136 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-688136.1 The deubiquitinase A20 is a negative feedback regulator of inflammatory responses, induced by NFkappaB activation (Krikos et al. 1992) and NOD stimulation (Masumoto et al. 2006). A20 can deubiquitinate RIP2 and restricts NOD2 induced signals (Hitosumatsu et al. 2008). 18342009 Pubmed 2008 The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals Hitotsumatsu, O Ahmad, RC Tavares, R Wang, M Philpott, D Turer, EE Lee, BL Shiffin, N Advincula, R Malynn, BA Werts, C Ma, A Immunity 28:381-90 1381359 Pubmed 1992 Transcriptional activation of the tumor necrosis factor alpha-inducible zinc finger protein, A20, is mediated by kappa B elements Krikos, A Laherty, CD Dixit, VM J Biol Chem 267:17971-6 16418393 Pubmed 2006 Nod1 acts as an intracellular receptor to stimulate chemokine production and neutrophil recruitment in vivo Masumoto, J Yang, K Varambally, S Hasegawa, M Tomlins, SA Qiu, S Fujimoto, Y Kawasaki, A Foster, SJ Horie, Y Mak, TW Nunez, G Chinnaiyan, AM Fukase, K Inohara, N J Exp Med 203:203-13 inferred by electronic annotation IEA GO IEA K63 polyubiquitinated RIP2 associates with the TAK1 complex K63 polyubiquitinated RIP2 associates with the TAK1 complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764164 1 Reactome DB_ID: 9787387 1 plasma membrane GO 0005886 TAK1 complex [plasma membrane] TAK1 complex Reactome DB_ID: 9764080 1 UniProt:Q62073 Map3k7 Map3k7 Tak1 Map3k7 FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR) (PubMed:10748100, PubMed:16157589, PubMed:21183079, PubMed:29291351). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK (PubMed:16157589, PubMed:8533096, PubMed:29291351). MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis (PubMed:10748100). In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity (By similarity). Phosphorylates RIPK1 at 'Ser-321' which positively regulates RIPK1 interaction with RIPK3 to promote necroptosis but negatively regulates RIPK1 kinase activity and its interaction with FADD to mediate apoptosis (PubMed:28842570).ACTIVITY REGULATION Activated by proinflammatory cytokines and in response to physical and chemical stresses, including osmotic stress, oxidative stress, arsenic and ultraviolet light irradiation. Activated by 'Lys-63'-linked polyubiquitination and by autophosphorylation. Association with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 promotes activation through autophosphorylation, whereas PPM1B/PP2CB, PP2A and PPP6C dephosphorylation leads to inactivation.SUBUNIT Can form homodimer (By similarity). Binds both upstream activators and downstream substrates in multimolecular complexes (By similarity). Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3 (By similarity). Identified in the TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 (By similarity). Interacts with PPM1L and PPM1B/PP2CB (PubMed:12556533). Interaction with PP2A and PPP6C leads to its repressed activity (By similarity). Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling (By similarity). Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation (By similarity). Interacts with DYNC2I2 (via WD domains) (By similarity). Interacts with CYLD and RBCK1 (PubMed:17548520). Interacts with TGFBR1; induces MAP3K7/TAK1 activation by TRAF6 (By similarity). Interacts with MAPK8IP1 and SMAD6 (PubMed:10748100, PubMed:17709393). Interacts with isoform 1 of VRK2 (PubMed:17709393). Interacts with DAB2; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation (By similarity). Interacts with TRIM5 (By similarity). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (PubMed:25632008). Interacts with PLEKHM1 (via N- and C-terminus) (PubMed:27777970). Interacts with TRIM8 (By similarity). Found in a complex with SH3RF1, RAC2, MAP2K7/MKK7, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2 (PubMed:27084103). Interacts with SASH1 (By similarity). Interacts with RIPK1 (PubMed:31519887).PTM Association with TAB1/MAP3K7IP1 promotes autophosphorylation and subsequent activation. Association with TAB2/MAP3K7IP2, itself associated with free unanchored Lys-63 polyubiquitin chain, promotes autophosphorylation and subsequent activation of MAP3K7. Dephosphorylation at Thr-187 by PP2A and PPP6C leads to inactivation (By similarity).PTM 'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation (PubMed:16157589). Undergoes 'Lys-48'-linked polyubiquitination catalyzed by ITCH (PubMed:25632008). 'Lys-63'-linked polyubiquitination at Lys-158 by TRIM8 does not lead to proteasomal degradation but contributes to autophosphorylation and activation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains (PubMed:17548520, PubMed:29291351).SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. UniProt Q62073 1 EQUAL 606 EQUAL Reactome DB_ID: 9764083 1 UniProt:Q8CF89 Tab1 Tab1 Map3k7ip1 Tab1 FUNCTION May be an important signaling intermediate between TGFB receptors and MAP3K7/TAK1. May play an important role in mammalian embryogenesis.SUBUNIT Interacts with XIAP and BIRC7. Interacts with TRAF6 and MAP3K7; during IL-1 signaling. Identified in the TRIKA2 complex composed of MAP3K7, TAB1 and TAB2 (By similarity).PTM Monoubiquitinated.CAUTION Lacks several key residues involved in metal-binding and catalytic activity, therefore has lost phosphatase activity. UniProt Q8CF89 1 EQUAL 504 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9787385 1 TAB2,TAB3 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Tab2 [plasma membrane] Tab3 [plasma membrane] UniProt Q99K90 UniProt Q571K4 Reactome Database ID Release 78 9787387 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787387 Reactome R-MMU-8947970 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8947970.1 Reactome DB_ID: 9787389 1 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:TAK1 complex [plasma membrane] PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:TAK1 complex Reactome DB_ID: 9764164 1 Reactome DB_ID: 9787387 1 Reactome Database ID Release 78 9787389 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787389 Reactome R-MMU-706478 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-706478.1 Reactome Database ID Release 78 9787391 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787391 Reactome R-MMU-688985 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-688985.1 K63-polyubiquitinated RIP2 is able to recruit the components of the TAK1 complex, which consists of TAK1, TAB1 and TAB2. inferred by electronic annotation IEA GO IEA TAK1 is activated TAK1 is activated This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9787389 1 Reactome DB_ID: 9764166 1 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complex [cytosol] PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complex Reactome DB_ID: 9764094 1 TAK1 complex [cytosol] TAK1 complex Converted from EntitySet in Reactome Reactome DB_ID: 9764092 1 TAB2,TAB3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Tab2 [cytosol] Tab3 [cytosol] Reactome DB_ID: 9764080 1 1 EQUAL 606 EQUAL Reactome DB_ID: 9764083 1 1 EQUAL 504 EQUAL Reactome Database ID Release 78 9764094 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764094 Reactome R-MMU-446878 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-446878.1 Reactome DB_ID: 9764164 1 Reactome Database ID Release 78 9764166 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764166 Reactome R-MMU-706477 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-706477.1 Reactome Database ID Release 78 9787393 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787393 Reactome R-MMU-706479 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-706479.1 The TAK1 complex consists of Transforming growth factor-beta (TGFB)-activated kinase (TAK1) and TAK1-binding protein 1 (TAB1), TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya et al. 1996, Sakurai et al. 2000). TAB1 promotes TAK1 autophosphorylation at the kinase activation lobe, probably through an allosteric mechanism (Brown et al. 2005, Ono et al. 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes to the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that lead to TAK1 activation. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004). 10702308 Pubmed 2000 TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop Kishimoto, K Matsumoto, K Ninomiya-Tsuji, J J Biol Chem 275:7359-64 14633987 Pubmed 2003 Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling Ishitani, T Takaesu, G Ninomiya-Tsuji, J Shibuya, H Gaynor, RB Matsumoto, K EMBO J 22:6277-88 15327770 Pubmed 2004 TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains Kanayama, A Seth, RB Sun, L Ea, CK Hong, M Shaito, A Chiu, YH Deng, L Chen, ZJ Mol Cell 15:535-48 inferred by electronic annotation IEA GO IEA 2.7.11.25 Activated TAK1 mediates phosphorylation of the IKK Complex Activated TAK1 mediates phosphorylation of the IKK Complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764054 1 CHUK:IKBKB:IKBKG [cytosol] CHUK:IKBKB:IKBKG Reactome DB_ID: 9764052 1 UniProt:O88351 Ikbkb UniProt O88351 1 EQUAL 756 EQUAL Reactome DB_ID: 9763953 1 1 EQUAL 419 EQUAL Reactome DB_ID: 9764050 1 UniProt:Q60680 Chuk UniProt Q60680 1 EQUAL 745 EQUAL Reactome Database ID Release 78 9764054 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764054 Reactome R-MMU-168113 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-168113.1 Reactome DB_ID: 113592 4 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 29370 4 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 9763967 1 IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKB [cytosol] IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKB Reactome DB_ID: 9763953 1 1 EQUAL 419 EQUAL Reactome DB_ID: 9763959 1 O-phospho-L-serine at 176 (in Homo sapiens) 176 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-serine at 180 (in Homo sapiens) 180 EQUAL 1 EQUAL 745 EQUAL Reactome DB_ID: 9763965 1 O-phospho-L-serine at 177 (in Homo sapiens) 177 EQUAL O-phospho-L-serine at 181 (in Homo sapiens) 181 EQUAL 1 EQUAL 756 EQUAL Reactome Database ID Release 78 9763967 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9763967 Reactome R-MMU-177663 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-177663.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9764182 Activated TAK complexes [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0004709 GO molecular function Reactome Database ID Release 78 9764183 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764183 Reactome Database ID Release 78 9764185 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764185 Reactome R-MMU-168184 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-168184.1 In humans, the IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. The IKK complex contains two catalytic subunits, IKK alpha and IKK beta associated with a regulatory subunit, NEMO (IKKgamma). The activation of the IKK complex and the NFkB mediated antiviral response are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the ubiquitination of NEMO [Solt et al 2009; Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta; it is unclear if NEMO subunit undergoes K63-linked or linear ubiquitination.<p>This basic trimolecular complex is referred to as the IKK complex. Each catalytic IKK subunit has an N-terminal kinase domain and leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-terminal NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs.<p>IKK beta is the major IKK catalytic subunit for NF-kB activation. Phosphorylation in the activation loop of IKK beta requires Ser177 and Ser181 and thus activates the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation. 11460167 Pubmed 2001 TAK1 is a ubiquitin-dependent kinase of MKK and IKK Wang, C Deng, L Hong, M Akkaraju, GR Inoue, J Chen, ZJ Nature 412:346-51 19666475 Pubmed 2009 The nemo binding domains of both IKKalpha and IKKbeta regulate IKK complex assembly and classical NFkappaB activation Solt, LA Madge, LA May, MJ J Biol Chem 9744859 Pubmed 1998 Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and death Arch, RH Gedrich, RW Thompson, CB Genes Dev 12:2821-30 17496917 Pubmed 2007 Ubiquitin-mediated activation of TAK1 and IKK Adhikari, A Xu, M Chen, ZJ Oncogene 26:3214-26 12221085 Pubmed 2002 IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response program Li, X Massa, PE Hanidu, A Peet, GW Aro, P Savitt, A Mische, S Li, J Marcu, KB J Biol Chem 277:45129-40 inferred by electronic annotation IEA GO IEA 2.7.11.25 TAK1 phosphorylates MKK6 TAK1 phosphorylates MKK6 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 2 Reactome DB_ID: 9785425 1 UniProt:P70236 Map2k6 Map2k6 Prkmk6 Sapkk3 Map2k6 FUNCTION Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 and MAPK14 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also phosphorylates and activates PAK6. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Nuclear targets of p38 MAP kinase include the transcription factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway, MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14 activation, and is therefore required for STAT4 activation and STAT4-regulated gene expression in response to IL-12 stimulation. The pathway is also crucial for IL-6-induced SOCS3 expression and down-regulation of IL-6-mediated gene induction; and for IFNG-dependent gene transcription. Has a role in osteoclast differentiation through NF-kappa-B transactivation by TNFSF11, and in endochondral ossification and since SOX9 is another likely downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts also as a regulator for melanocytes dendricity, through the modulation of Rho family GTPases.ACTIVITY REGULATION Activated by dual phosphorylation on Ser-207 and Thr-211 in response to a variety of cellular stresses, including UV radiation, osmotic shock, hypoxia, inflammatory cytokines, interferon gamma (IFNG), and less often by growth factors. MAP2K6/MKK6 is activated by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2.SUBUNIT Dimer. Interacts (via its D domain) with its substrates MAPK11, MAPK12, MAPK13 and MAPK14. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2. Interacts with DCTN1. Interacts with EIF2AK2/PKR.INDUCTION MSAPK14 can negatively regulate the stability of the MAP2K6/MKK6 mRNA and thus control the steady-state concentration of one of its upstream activator.DOMAIN The DVD domain (residues 311-334) contains a conserved docking site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAP3Ks) and are essential for activation (By similarity).DOMAIN The D domain (residues 4-19) contains a conserved docking site and is required for the binding to MAPK substrates.PTM Weakly autophosphorylated. Phosphorylated at Ser-207 and Thr-211 by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. UniProt P70236 1 EQUAL 334 EQUAL Reactome DB_ID: 29370 2 Reactome DB_ID: 532220 1 O-phospho-L-serine at 207 207 EQUAL O-phospho-L-threonine at 211 211 EQUAL O-phospho-L-threonine [MOD:00047] 1 EQUAL 334 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9764094 Reactome Database ID Release 78 9787428 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787428 Reactome Database ID Release 78 9787430 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787430 Reactome R-MMU-727819 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-727819.1 Within the TAK1 complex (TAK1 plus TAB1 and TAB2/3) activated TAK1 phosphorylates IKKB, MAPK kinase 6 (MKK6) and other MAPKs to activate the NFkappaB and MAPK signaling pathways. TAB2 within the TAK1 complex can be linked to polyubiquitinated TRAF6; current models of IL-1 signaling suggest that the TAK1 complex is linked to TRAF6, itself complexed with polyubiquitinated IRAK1 which is linked via NEMO to the IKK complex. The TAK1 complex is also essential for NOD signaling; NOD receptors bind RIP2 which recruits the TAK1 complex (Hasegawa et al. 2008). inferred by electronic annotation IEA GO IEA NOD1 induced apoptosis is mediated by RIP2 and CARD8 NOD1 induced apoptosis is mediated by RIP2 and CARD8 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9787341 1 Long prodomain caspases [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Casp8 [cytosol] UniProt O89110 Reactome DB_ID: 9764149 1 Reactome DB_ID: 9787343 1 NOD1:iE-DAP:Long prodomain caspases [cytosol] NOD1:iE-DAP:Long prodomain caspases Converted from EntitySet in Reactome Reactome DB_ID: 9787341 1 Reactome DB_ID: 9764149 1 Reactome Database ID Release 78 9787343 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787343 Reactome R-MMU-622417 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-622417.1 Reactome Database ID Release 78 9787345 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787345 Reactome R-MMU-622420 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-622420.1 NOD1 was found to coimmunoprecipitate with several procaspases containing long prodomains with CARDs or DEDs, including caspase-1, caspase-2, caspase-4, caspase-8, and caspase-9, but not those with short prodomains like caspase-3 or caspase-7. Deletions of caspase-9 determined that the CARD domain was required for this interaction (Inohara et al. 1999). More recently, NOD1 activation of apoptosis was shown to require the RIP2-dependent activation of caspase-8, this effect being inhibited by CASP8 and FADD-like apoptosis regulator, also called FLICE-inhibitory protein, FLIP or CLARP (da Silva Correia et al. 2007), which is a specific inhibitor of caspase-8 (Irmler et al. 1997). 9217161 Pubmed 1997 Inhibition of death receptor signals by cellular FLIP Irmler, M Thome, M Hahne, M Schneider, P Hofmann, K Steiner, V Bodmer, JL Schröter, M Burns, K Mattmann, C Rimoldi, D French, LE Tschopp, Jürg Nature 388:190-5 17186025 Pubmed 2007 Regulation of Nod1-mediated signaling pathways da Silva Correia, J Miranda, Y Leonard, N Hsu, J Ulevitch, RJ Cell Death Differ 14:830-9 inferred by electronic annotation IEA GO IEA 2.7.12.2 Activation of p38 MAPK Activation of p38 MAPK This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9796606 1 p38 MAPK [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 113592 8 Reactome DB_ID: 29370 8 Converted from EntitySet in Reactome Reactome DB_ID: 9796610 1 Phospho-p38 MAPK [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 532220 O-phospho-L-serine at 207 207 EQUAL O-phospho-L-threonine at 211 211 EQUAL 1 EQUAL 334 EQUAL GO 0004708 GO molecular function Reactome Database ID Release 78 532223 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=532223 Reactome Database ID Release 78 9796612 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9796612 Reactome R-MMU-1247960 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-1247960.1 p38 MAPK has 4 representative isoforms in humans, p38 alpha (Han et al. 1993), p38-beta (Jiang et al. 1996), p38-gamma (Lechner et al. 1996) and p38-delta (Hu et al. 1999). All are activated by phosphorylation on a canonical TxY motif by the dual-specificity kinase MKK6, which displays minimal substrate selectivity amongst the p38 isoforms (Zarubin & Han, 2005). p38 alpha and gamma are also activated by MKK3. 15686620 Pubmed 2005 Activation and signaling of the p38 MAP kinase pathway Zarubin, T Han, J Cell Res 15:11-8 7693711 Pubmed 1993 Endotoxin induces rapid protein tyrosine phosphorylation in 70Z/3 cells expressing CD14 Han, J Lee, JD Tobias, PS Ulevitch, RJ J Biol Chem 268:25009-14 9430721 Pubmed 1998 Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6 Enslen, H Raingeaud, J Davis, RJ J Biol Chem 273:1741-8 8633070 Pubmed 1996 ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation Lechner, C Zahalka, MA Giot, JF Møller, NP Ullrich, A Proc Natl Acad Sci U S A 93:4355-9 8663524 Pubmed 1996 Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta) Jiang, Y Chen, C Li, Z Guo, W Gegner, JA Lin, S Han, J J Biol Chem 271:17920-6 10066767 Pubmed 1999 Murine p38-delta mitogen-activated protein kinase, a developmentally regulated protein kinase that is activated by stress and proinflammatory cytokines Hu, MC Wang, YP Mikhail, A Qiu, WR Tan, TH J Biol Chem 274:7095-102 inferred by electronic annotation IEA GO IEA AAMP binds NOD2 AAMP binds NOD2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764154 1 1 EQUAL 1040 EQUAL Reactome DB_ID: 9858271 1 UniProt:J3QN89 Aamp UniProt J3QN89 1 EQUAL 434 EQUAL Reactome DB_ID: 9858314 1 AAMP:NOD2 [cytosol] AAMP:NOD2 Reactome DB_ID: 9764154 1 1 EQUAL 1040 EQUAL Reactome DB_ID: 9858271 1 1 EQUAL 434 EQUAL Reactome Database ID Release 78 9858314 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9858314 Reactome R-MMU-9676152 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9676152.1 Reactome Database ID Release 78 9858316 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9858316 Reactome R-MMU-9676160 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9676160.1 AAMP (Angio-associated migratory cell protein) binds the human nucleotide-binding domain, leucine rich repeat containing (NLR) family member NOD2. The interaction involves WD40 domains 2-4 of AAMP. NOD2 is critically involved in innate immune protection against a variety of different bacterial pathogens. AAMP negatively regulates, through an unknown mechanism, NOD2-mediated NF-κB activation in HEK293T cells (Bielig et al. 2009). 19535145 Pubmed 2009 A function for AAMP in Nod2-mediated NF-kappaB activation Bielig, H Zurek, B Kutsch, A Menning, M Philpott, D J Sansonetti, P J Kufer, T A Mol. Immunol. 46:2647-54 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9860874 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860874 Reactome R-MMU-168638 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-168638.1 GO 0070423 GO biological process NOD1 is ubiquitously expressed, while NOD2 expression is restricted to monocytes, macrophages, dendritic cells, and intestinal Paneth cells (Inohara et al. 2005). NOD1 and NOD2 activation induces transcription of immune response genes, predominantly mediated by the proinflammatory transcriptional factor NFkappaB but also by AP-1 and Elk-1 (Inohara et al. 2005). NFkappaB translocates to the nucleus following release from IkappaB proteins. NOD1 and NOD2 signaling involves an interaction between their caspase-recruitment domain (CARD) and the CARD of the kinase RIPK2 (RIP2/RICK). This leads to the activation of the NFkappaB pathway and MAPK pathways (Windheim et al. 2007).<br>Activated NODs oligomerize via their NACHT domains, inducing physical proximity of RIP2 proteins that is believed to trigger their K63-linked polyubiquitination, facilitating recruitment of the TAK1 complex. RIP2 also recruits NEMO, bringing the TAK1 and IKK complexes into proximity, leading to NF-kappaB activation and activation of MAPK signaling. Recent studies have demonstrated that K63-linked regulatory ubiquitination of RIP2 is essential for the recruitment of TAK1 (Hasegawa et al. 2008, Hitosumatsu et al. 2008). As observed for toll-like receptor (TLR) signaling, ubiquitination can be removed by the deubiquitinating enzyme A20, thereby dampening NOD1/NOD2-induced NF-kappaB activation. NOD1 and NOD2 both induce K63-linked ubiquitination of RIP2, but NOD2-signaling appears to preferentially utilize the E3 ligase TRAF6, while TRAF2 and TRAF5 were shown to be important for NOD1-mediated signaling. In both cases, activation of NF-kappaB results in the upregulated transcription and production of inflammatory mediators. 15952891 Pubmed 2005 NOD-LRR proteins: role in host-microbial interactions and inflammatory disease Inohara, N Chamaillard, M McDonald, C Nunez, G Annu Rev Biochem 74:355-83 18928408 Pubmed 2009 NOD-like receptors: role in innate immunity and inflammatory disease Chen, G Shaw, MH Kim, YG Nunez, G Annu Rev Pathol 4:365-98 18585455 Pubmed 2008 NOD-like receptors (NLRs): bona fide intracellular microbial sensors Shaw, MH Reimer, T Kim, YG Nunez, G Curr Opin Immunol 20:377-82 18414735 Pubmed 2008 Signal transduction pathways used by NLR-type innate immune receptors Kufer, TA Mol Biosyst 4:380-6 inferred by electronic annotation IEA GO IEA Inflammasomes Inflammasomes This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> The NLRP3 inflammasome The NLRP3 inflammasome This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> P2X7 mediates loss of intracellular K+ P2X7 mediates loss of intracellular K+ This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29804 1 potassium(1+) [ChEBI:29103] potassium(1+) K+ Potassium ChEBI 29103 Reactome DB_ID: 74126 1 extracellular region GO 0005576 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9787727 ATP:P2X7 oligomer [plasma membrane] ATP:P2X7 oligomer Reactome DB_ID: 9787725 3 ATP:P2X7 [plasma membrane] ATP:P2X7 Reactome DB_ID: 9759984 1 UniProt:Q9Z1M0 P2rx7 UniProt Q9Z1M0 1 EQUAL 595 EQUAL Reactome DB_ID: 114570 1 Reactome Database ID Release 78 9787725 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787725 Reactome R-MMU-877166 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-877166.1 Reactome Database ID Release 78 9787727 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787727 Reactome R-MMU-877257 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-877257.1 GO 0004931 GO molecular function Reactome Database ID Release 78 9787728 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787728 Reactome Database ID Release 78 9787730 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787730 Reactome R-MMU-877187 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-877187.1 Low level or transient activation of P2X7 leads to reversible opening of a membrane channel permeable to small cations such as Na+, Ca2+ and K+ (Adinolfi et al. 2005). 9023774 Pubmed 1997 Purinoceptor-operated cationic channels in human B lymphocytes Markwardt, F Lohn, Matthias Bohm, Thomas Klapperstuck, M J Physiol 498:143-51 11157473 Pubmed 2001 Nucleotide receptors: an emerging family of regulatory molecules in blood cells Di Virgilio, F Chiozzi, P Ferrari, D Falzoni, S Sanz, JM Morelli, A Torboli, M Bolognesi, G Baricordi, OR Blood 97:587-600 18404507 Pubmed 2005 P2X(7) receptor: Death or life? Adinolfi, E Pizzirani, C Idzko, M Panther, E Norgauer, J Di Virgilio, F Ferrari, D Purinergic Signal 1:219-27 inferred by electronic annotation IEA GO IEA P2X7 mediates membrane pores that include pannexin-1 P2X7 mediates membrane pores that include pannexin-1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9787727 1 Reactome DB_ID: 9776511 1 UniProt:Q9JIP4 Panx1 UniProt Q9JIP4 1 EQUAL 426 EQUAL Reactome DB_ID: 9787732 1 ATP:P2X7 oligomer:Pannexin-1 [plasma membrane] ATP:P2X7 oligomer:Pannexin-1 Reactome DB_ID: 9787727 1 Reactome DB_ID: 9776511 1 1 EQUAL 426 EQUAL Reactome Database ID Release 78 9787732 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787732 Reactome R-MMU-877242 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-877242.1 Reactome Database ID Release 78 9787734 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787734 Reactome R-MMU-877198 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-877198.1 At higher concentrations of extracellular ATP, the P2X7 channel acts as an inducer of nonselective macropores permeable to large (up to 800 Da) inorganic and organic molecules. These 'death complex' pores rapidly leads to complete collapse of ionic gradients, changing the cytosolic environment from high K/ low Na/ low Cl to low K/ high Na/ high Cl (Steinberg et al. 1987, Steinberg & Silverstein 1987, Kahlenberg & Dubyak 2004). The long carboxyl-terminal cytoplasmic domain of P2X7 (352-595) appears to be crucial for P2X7 pore formation (Cheewatrakoolpong et al. 2005, Adinolfi et al. 2005). P2X7 membrane pores were recently shown to include pannexin-1 (Locovei et al. 2007). Pannexins have low homology with the invertebrate innexin gap junction proteins, reported to form gap junction channels and also to function as hemi-gap junction channels that are sensitive to gap junction channel blockers (Bruzzone et al. 2003, 2005). The P2X7 receptor is generally accepted to be part of a multimeric complex, not fully characterized (Kim et al. 2001). 3597398 Pubmed 1987 ATP4- permeabilizes the plasma membrane of mouse macrophages to fluorescent dyes Steinberg, TH Newman, AS Swanson, JA Silverstein, SC J Biol Chem 262:8884-8 15075209 Pubmed 2004 Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release Kahlenberg, JM Dubyak, GR Am J Physiol Cell Physiol 286:C1100-8 2182768 Pubmed 1990 ATP-induced pore formation in the plasma membrane of rat peritoneal mast cells Tatham, PE Lindau, M J Gen Physiol 95:459-76 14597722 Pubmed 2003 Pannexins, a family of gap junction proteins expressed in brain Bruzzone, R Hormuzdi, SG Barbe, MT Herb, A Monyer, H Proc Natl Acad Sci U S A 100:13644-9 15715654 Pubmed 2005 Pharmacological properties of homomeric and heteromeric pannexin hemichannels expressed in Xenopus oocytes Bruzzone, R Barbe, MT Jakob, NJ Monyer, H J Neurochem 92:1033-43 450099 Pubmed 1979 ATP induces nucleotide permeability in rat mast cells Cockcroft, S Gomperts, BD Nature 279:541-2 17240370 Pubmed 2007 Pannexin1 is part of the pore forming unit of the P2X(7) receptor death complex Locovei, S Scemes, E Qiu, F Spray, DC Dahl, G FEBS Lett 581:483-8 11707406 Pubmed 2001 Proteomic and functional evidence for a P2X7 receptor signalling complex Kim, M Jiang, LH Wilson, HL North, RA Surprenant, A EMBO J 20:6347-58 17036048 Pubmed 2006 Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor Pelegrin, P Surprenant, A EMBO J 25:5071-82 15896293 Pubmed 2005 Identification and characterization of splice variants of the human P2X7 ATP channel Cheewatrakoolpong, B Gilchrest, H Anthes, JC Greenfeder, S Biochem Biophys Res Commun 332:17-27 inferred by electronic annotation IEA GO IEA SGT1 binds HSP90 SGT1 binds HSP90 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9781470 1 UniProt:P11499 Hsp90ab1 UniProt P11499 2 EQUAL 724 EQUAL Reactome DB_ID: 9787715 1 UniProt:Q9CX34 Sugt1 UniProt Q9CX34 2 EQUAL 365 EQUAL Reactome DB_ID: 9787717 1 SUGT1:HSP90 [cytosol] SUGT1:HSP90 Reactome DB_ID: 9781470 1 2 EQUAL 724 EQUAL Reactome DB_ID: 9787715 1 2 EQUAL 365 EQUAL Reactome Database ID Release 78 9787717 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787717 Reactome R-MMU-874112 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-874112.1 Reactome Database ID Release 78 9787723 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787723 Reactome R-MMU-874087 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-874087.1 The ubiquitin ligase–associated protein SGT1 (SUGT1) has two putative HSP90 binding domains, a tetratricopeptide repeat and a p23-like CHORD and Sgt1 (CS) domain. The CS domain of human SGT1 physically interacts with HSP90. SGT1 and related proteins are believed to recruit heat shock proteins to multiprotein assemblies (Lee et al. 2004). 14761955 Pubmed 2004 Human Sgt1 binds HSP90 through the CHORD-Sgt1 domain and not the tetratricopeptide repeat domain Lee, YT Jacob, J Michowski, W Nowotny, M Kuznicki, J Chazin, WJ J Biol Chem 279:16511-7 inferred by electronic annotation IEA GO IEA SGT1:HSP90 binds inactive NLRP3 SGT1:HSP90 binds inactive NLRP3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9787717 1 Reactome DB_ID: 9787711 1 UniProt:Q8R4B8 Nlrp3 Nlrp3 Mmig1 Nalp3 Pypaf1 Cias1 Nlrp3 FUNCTION As the sensor component of the NLRP3 inflammasome, plays a crucial role in innate immunity and inflammation. In response to pathogens and other damage-associated signals, initiates the formation of the inflammasome polymeric complex, made of NLRP3, PYCARD and CASP1 (or possibly CASP4/CASP11). Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu (PubMed:28847925, PubMed:27374331). Activation of NLRP3 inflammasome is also required for HMGB1 secretion (PubMed:22801494). The active cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death. Under resting conditions, NLRP3 is autoinhibited. NLRP3 activation stimuli include extracellular ATP, reactive oxygen species, K(+) efflux, crystals of monosodium urate or cholesterol, amyloid-beta fibers, environmental or industrial particles and nanoparticles, cytosolic dsRNA, etc. However, it is unclear what constitutes the direct NLRP3 activator. Activation in presence of cytosolic dsRNA is mediated by DHX33 (By similarity). Independently of inflammasome activation, regulates the differentiation of T helper 2 (Th2) cells and has a role in Th2 cell-dependent asthma and tumor growth. During Th2 differentiation, required for optimal IRF4 binding to IL4 promoter and for IRF4-dependent IL4 transcription. Binds to the consensus DNA sequence 5'-GRRGGNRGAG-3'. May also participate in the transcription of IL5, IL13, GATA3, CCR3, CCR4 and MAF (PubMed:26098997).SUBUNIT Sensor component of NLRP3 inflammasomes. Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation. The core of NLRP3 inflammasomes consists of a signal sensor component (NLRP3), an adapter (ASC/PYCARD), which recruits an effector proinflammatory caspase (CASP1 and, possibly, CASP4 and CASP5). Within the complex, NLRP3 and PYCARD interact via their respective pyrin domains. This interaction initiates speck formation (nucleation) which greatly enhances further addition of soluble PYCARD molecules to the speck in a prion-like polymerization process. NLRP3 localizes at the end of each PYCARD filament. Clustered PYCARD nucleates the formation of CASP1 filaments through the interaction of their respective CARD domains, acting as a platform for CASP1 polymerization. CASP1 filament formation increases local enzyme concentration, resulting in trans-autocleavage and activation. Active CASP1 then processes IL1B and IL18 precursors, leading to the release of mature cytokines in the extracellular milieu and inflammatory response. Reconstituted ternary inflammasomes show star-shaped structures, in which multiple filaments, containing CASP1, protrude radially from a single central hub, containing the sensor protein and PYCARD. In this complex, the sensor protein is sub-stoichiometric to PYCARD, and PYCARD is further substoichiometric to CASP1, suggesting amplifications of signal transduction from the sensor, via the adapter, to the effector (By similarity). Interacts with MEFV; this interaction targets NLRP3 to degradation by autophagy, hence preventing excessive IL1B- and IL18-mediated inflammation (By similarity). Interacts with GBP5 (via DAPIN domain); this interaction promotes inflammasome assembly in response to microbial and soluble, but not crystalline, agents (By similarity). Interacts with EIF2AK2/PKR; this interaction requires EIF2AK2 activity, is accompanied by EIF2AK2 autophosphorylation and promotes inflammasome assembly in response to specific stimuli (PubMed:22801494). Interacts with PML (isoform PML-1) (via the LRR region); PML-mediated increase in NLRP3 inflammasome activation does not depend upon this interaction. Directly interacts with IRF4 (via LRR region); this interaction is required for optimal IRF4 binding to IL4 promoter and efficient IL4 transactivation during differentiation of Th2 helper T-cells (PubMed:26098997). Interacts (via NACHT domain) with DHX33 (via DEAH box) (By similarity). Interacts with PYDC5 (By similarity). Interacts (via NACHT domain) with DDX3X under both LPS-primed and inflammasome-activating conditions (PubMed:31511697). Interacts (via NACHT and LRR domains) with ARRB2; this interaction is direct and inducible by omega-3 polyunsaturated fatty acids (PUFAs).TISSUE SPECIFICITY Expressed with high levels in peripheral blood leukocytes, including Th2 lymphocytes and macrophages (PubMed:15302403, PubMed:26098997, PubMed:16546100, PubMed:28847925). Expressed at low levels in resting osteoblasts (at protein level) (PubMed:17907925).DEVELOPMENTAL STAGE Up-regulated during CD4(+) T-lymphocyte differentiation, in Th0, Th1 and Th2 cells. Not detected in naive CD4(+) T-lymphocytes (at protein level).INDUCTION By activators of Toll-like receptors, such as lipoteichoic acid (LTA) (TLR2), polyinosine-polycytidylic acid (poly(I:C), a synthetic analog of dsRNA) (TLR3) and bacterial lipopolysaccharides (LPS) (TLR4) (PubMed:16546100). Up-regulated by IL2 via STAT5 signaling (PubMed:26098997). Slightly up-regulated in osteoblasts after exposure to invasive, but not invasion-defective, strains of Salmonella typhimurium (at protein level) (PubMed:17907925).DOMAIN The LRR domain mediates the interaction with IRF4 and PML.DOMAIN Intramolecular interactions between NACHT and leucine-rich repeat (LRR) domains may be important for autoinhibition in the absence of activating signal.DOMAIN The pyrin domain (also called DAPIN domain or PYD) is involved in PYCARD-binding.PTM Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. Ubiquitination does not lead to degradation, but inhibits inflammasome activation (PubMed:23246432). Deubiquitination is catalyzed by BRCC3 and associated with NLRP3 activation and inflammasome assembly. This process can be induced by the activation of Toll-like receptors (by LPS), through a non-transcriptional pathway dependent on the mitochondrial production of reactive oxygen species, and by ATP.PTM The disulfide bond in the pyrin domain might play a role in reactive oxygen species-mediated activation.DISRUPTION PHENOTYPE Knockout mice are fertile and appear healthy when housed in a standard specific pathogen-free environment. They do not exhibit any increase in serum IL1B after administration of R837 (an analog to guanosine and TLR7 agonist) and/or LPS (PubMed:16407890) (PubMed:16407888). When challenged with LPS, mutant mice are partially resistant to endotoxic shock (PubMed:16546100) (PubMed:16407890). Mutant mice display impaired contact hypersensitivity, a T-cell-mediated cellular immune response to repeated epicutaneous exposure to contact allergens, such as trinitrophenylchloride (PubMed:16546100). In a model of allergic asthma that promotes strictly Th2 responses, mutant animals show less infiltration of eosinophils and lymphocytes into the lungs than their wild-type counterparts, as well as less accumulation of mucus and lymphoid infiltrates. The concentration of Th2 cell-related cytokines, including IL-5 and IL-4, is also lower in lungs from mutant mice compared to wild-type (PubMed:26098997). Knockout mice develop insulin (INS) resistance in response to high-fat diet.MISCELLANEOUS Expression is increased in mice with experimental atopic dermatitis.SIMILARITY Belongs to the NLRP family. UniProt Q8R4B8 1 EQUAL 1036 EQUAL Reactome DB_ID: 9787719 1 NLRP3:SUGT1:HSP90 [cytosol] NLRP3:SUGT1:HSP90 Reactome DB_ID: 9787717 1 Reactome DB_ID: 9787711 1 1 EQUAL 1036 EQUAL Reactome Database ID Release 78 9787719 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787719 Reactome R-MMU-874086 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-874086.1 Reactome Database ID Release 78 9787721 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787721 Reactome R-MMU-873951 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-873951.1 SGT1 and HSP90 bind the NLRP3 (NALP3) LRR domain. Genetic studies in plants suggest a role for SGT1-HSP90 as co-chaperones of plant resistance (R) proteins, serving to maintain them in an inactive but signaling-competent state. R-protein activation is beleived to lead to dissociation of the SGT1-HSP90 complex. SGT1 and HSP90 are highly conserved, while R proteins are structurally related to mammalian NLRs. Human SGT1 and HSP90 were found to bind NLRP3 (Mayor et al. 2007). Knockdown of human SGT1 by small interfering RNA or chemical inhibition of HSP90 by geldanamycin abrogated NLRP3 inflammasome activity in human monocytic cell line THP-1 (Mayor et al. 2007). Similarly, NLRP3 inflammasome activation was abrogated in geldanamycin-treated human retinal pigment epithelial (RPE) cells (Piippo N et al. 2018). These data indicate that SGT1 and HSP90 are involved in regulation of NLRP3 inflammasome signaling (Mayor et al. 2007; Piippo N et al. 2018). 17435760 Pubmed 2007 A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses Mayor, A Martinon, F De Smedt, T Pétrilli, V Tschopp, Jürg Nat Immunol 8:497-503 29712950 Pubmed 2018 Hsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasome Piippo, Niina Korhonen, Eveliina Hytti, Maria Skottman, H Kinnunen, Kati Josifovska, Natasha Petrovski, Goran Kaarniranta, Kai Kauppinen, Anu Sci Rep 8:6720 inferred by electronic annotation IEA GO IEA TXNIP binds reduced thioredoxin TXNIP binds reduced thioredoxin This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9755249 1 UniProt:P10639 Txn Txn Txn1 Txn FUNCTION Participates in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyzes dithiol-disulfide exchange reactions (By similarity). Plays a role in the reversible S-nitrosylation of cysteine residues in target proteins, and thereby contributes to the response to intracellular nitric oxide. Nitrosylates the active site Cys of CASP3 in response to nitric oxide (NO), and thereby inhibits caspase-3 activity. Induces the FOS/JUN AP-1 DNA binding activity in ionizing radiation (IR) cells through its oxidation/reduction status and stimulates AP-1 transcriptional activity (By similarity).FUNCTION ADF augments the expression of the interleukin-2 receptor TAC (IL2R/P55).SUBUNIT Homodimer; disulfide-linked. Interacts with TXNIP through the redox-active site. Interacts with MAP3K5 and CASP3. Interacts with APEX1; the interaction stimulates the FOS/JUN AP-1 DNA-binding activity in a redox-dependent manner (By similarity).PTM In the fully reduced protein, both Cys-69 and Cys-73 are nitrosylated in response to nitric oxide (NO). When two disulfide bonds are present in the protein, only Cys-73 is nitrosylated. Cys-73 can serve as donor for nitrosylation of target proteins (By similarity).SIMILARITY Belongs to the thioredoxin family. UniProt P10639 2 EQUAL 105 EQUAL Reactome DB_ID: 9796692 1 UniProt:Q8BG60 Txnip Txnip Vdup1 Txnip FUNCTION May act as an oxidative stress mediator by inhibiting thioredoxin activity or by limiting its bioavailability. Interacts with COPS5 and restores COPS5-induced suppression of CDKN1B stability, blocking the COPS5-mediated translocation of CDKN1B from the nucleus to the cytoplasm. Inhibits the proteasomal degradation of DDIT4, and thereby contributes to the inhibition of the mammalian target of rapamycin complex 1 (mTORC1) (By similarity). Functions as a transcriptional repressor, possibly by acting as a bridge molecule between transcription factors and corepressor complexes, and over-expression will induce G0/G1 cell cycle arrest. Required for the maturation of natural killer cells. Acts as a suppressor of tumor cell growth.SUBUNIT Homodimer; disulfide-linked. Interacts with TXN/thioredoxin through its redox-active site. Interacts with transcriptional repressors ZBTB16, ZBTB32 and HDAC1. Interacts (via C-terminus) with ITCH (via WW domains). Interacts with DDIT4 (By similarity).TISSUE SPECIFICITY Ubiquitously expressed.PTM Ubiquitinated; undergoes polyubiquitination catalyzed by ITCH resulting in proteasomal degradation.DISRUPTION PHENOTYPE Marked reduction in the numbers of natural killer cells, low levels of Il2rb expression in the precursor hematopoietic stem cells and severe lymphoid hyperplasia in the small intestine.SIMILARITY Belongs to the arrestin family. UniProt Q8BG60 1 EQUAL 391 EQUAL Reactome DB_ID: 9796694 1 Thioredoxin:TXNIP [cytosol] Thioredoxin:TXNIP Reactome DB_ID: 9755249 1 2 EQUAL 105 EQUAL Reactome DB_ID: 9796692 1 1 EQUAL 391 EQUAL Reactome Database ID Release 78 9796694 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9796694 Reactome R-MMU-1250277 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-1250277.1 Reactome Database ID Release 78 9796696 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9796696 Reactome R-MMU-1250264 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-1250264.1 TXNIP interacts with the redox-active domain of thioredoxin (TRX) and is believed to act as an oxidative stress mediator by inhibiting TRX activity or by limiting its bioavailability (Nishiyama et al. 1999, Liyanage et al. 2007). 10419473 Pubmed 1999 Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expression Nishiyama, A Matsui, M Iwata, S Hirota, K Masutani, H Nakamura, H Takagi, Y Sono, H Gon, Y Yodoi, J J Biol Chem 274:21645-50 17603038 Pubmed 2007 Regulation of the bioavailability of thioredoxin in the lens by a specific thioredoxin-binding protein (TBP-2) Liyanage, NP Fernando, MR Lou, MF Exp Eye Res 85:270-9 inferred by electronic annotation IEA GO IEA ROS oxidize thioredoxin ROS oxidize thioredoxin This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 1250243 1 reactive oxygen species [ChEBI:26523] reactive oxygen species ChEBI 26523 Reactome DB_ID: 9755249 1 2 EQUAL 105 EQUAL Reactome DB_ID: 9755247 1 Intra-chain Crosslink via L-cystine (cross-link) at 32 and 35 (in Homo sapiens) 32 EQUAL L-cystine (cross-link) 2 EQUAL 105 EQUAL Reactome Database ID Release 78 9796698 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9796698 Reactome R-MMU-1250280 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-1250280.1 The presence of reactive oxygen species (ROS) leads to the oxidation of thioredoxin and consequent release of TXNIP (Zhou et al. 2010). The source of the ROS is unclear but they are known to be essential for caspase-1 activation (Cruz et al. 2007) and are produced in response to all known NLRP3 activators (Dostert et al. 2008, Zhou et al. 2010). The freed TXNIP binds NLRP3 and is proposed to activate the NLRP3 inflammasome, explaining how ROS can bring about NLRP3 activation. 20023662 Pubmed 2010 Thioredoxin-interacting protein links oxidative stress to inflammasome activation Zhou, R Tardivel, A Thorens, B Choi, I Tschopp, Jürg Nat Immunol 11:136-40 18403674 Pubmed 2008 Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica Dostert, C Pétrilli, V Van Bruggen, R Steele, C Mossman, BT Tschopp, Jürg Science 320:674-7 17132626 Pubmed 2007 ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages Cruz, CM Rinna, A Forman, HJ Ventura, AL Persechini, PM Ojcius, DM J Biol Chem 282:2871-9 inferred by electronic annotation IEA GO IEA NLRP3 activation by small molecules NLRP3 activation by small molecules This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9787719 1 Converted from EntitySet in Reactome Reactome DB_ID: 877245 1 NLRP3 elicitor small molecules [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity HUA [cytosol] SiO2 [cytosol] Asb [cytosol] ChEBI 16336 ChEBI 30563 ChEBI 46661 Reactome DB_ID: 9797398 1 NLRP3 elicitor small molecules:NLRP3 [cytosol] NLRP3 elicitor small molecules:NLRP3 Converted from EntitySet in Reactome Reactome DB_ID: 877245 1 Reactome DB_ID: 9787711 1 1 EQUAL 1036 EQUAL Reactome Database ID Release 78 9797398 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9797398 Reactome R-MMU-877226 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-877226.1 Reactome DB_ID: 9787717 1 Reactome Database ID Release 78 9797400 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9797400 Reactome R-MMU-1306876 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-1306876.1 The NLRP3 inflammasome is activated by a range of stimuli of microbial, endogenous and exogenous origins including several viruses, bacterial pore forming toxins (e.g. Craven et al. 2009), and various irritants that form crystalline or particulate structures (see Cassel et al. 2009). Multiple studies have shown that phagocytosis of particulate elicitors is necessary for activation (e.g. Hornung et al. 2008) but not for the response to ATP, which is mediated by the P2X7 receptor (Kahlenberg & Dubyak, 2004) and appears to involve the pannexin membrane channel (Pellegrin & Suprenenant 2006), which is also involved in the response to nigericin and maitotoxin (Pellegrin & Suprenenant 2007). Direct binding of elicitors to NLRP3 has not been demonstrated and the exact process of activation is unclear, though speculated to involve changes in conformation that make available the NACHT domain for oligomerization (Inohara & Nunez 2001, 2003).<br><br>Three overlapping mechanisms are believed to be involved in NLRP3 activation. ATP stimulates the P2X7 ATP-gated ion channel leading to K+ efflux which appears necessary for NLRP3 inflammasome activation (Kahlenberg & Dubyak 2004, Dostert et al. 2008), and is believed to induce formation of pannexin-1 membrane pores. These pores give direct access of NLPR3 agonists to the cytosol. A second mechanism is the endocytosis of crystalline or particulate structures, leading to damaged lysosomes which release their contents (Hornung et al. 2008, Halle et al. 2008). The third element is the generation of reactive oxygen species (ROS) which activate NLRP3, shown to be a critical step for the activation of caspase-1 following ATP stimulation (Cruz et al. 2007). The source of the ROS is unclear. 18280002 Pubmed 2008 Intracellular pattern-recognition receptors Dostert, C Meylan, E Tschopp, Jürg Adv Drug Deliv Rev 60:830-40 17121814 Pubmed 2007 Pannexin-1 couples to maitotoxin- and nigericin-induced interleukin-1beta release through a dye uptake-independent pathway Pelegrin, P Surprenant, A J Biol Chem 282:2386-94 12766759 Pubmed 2003 NODs: intracellular proteins involved in inflammation and apoptosis Inohara, N Nunez, G Nat Rev Immunol 3:371-82 20303873 Pubmed 2010 The inflammasomes Schroder, K Tschopp, Jürg Cell 140:821-32 19826485 Pubmed 2009 Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells Craven, RR Gao, X Allen, IC Gris, D Bubeck Wardenburg, J McElvania-Tekippe, E Ting, JP Duncan, JA PLoS One 4:e7446 19501527 Pubmed 2009 The NLRP3 inflammasome: a sensor of immune danger signals Cassel, SL Joly, S Sutterwala, FS Semin Immunol 21:194-8 11607846 Pubmed 2001 The NOD: a signaling module that regulates apoptosis and host defense against pathogens Inohara, N Nunez, G Oncogene 20:6473-81 18604209 Pubmed 2008 The NALP3 inflammasome is involved in the innate immune response to amyloid-beta Halle, A Hornung, V Petzold, GC Stewart, CR Monks, BG Reinheckel, Thomas Fitzgerald, Katherine A Latz, E Moore, KJ Golenbock, DT Nat Immunol 9:857-65 18604214 Pubmed 2008 Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization Hornung, V Bauernfeind, FG Halle, A Samstad, EO Kono, H Rock, KL Fitzgerald, Katherine A Latz, E Nat Immunol 9:847-56 inferred by electronic annotation IEA GO IEA PSTPIP1 binds Pyrin PSTPIP1 binds Pyrin This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9787768 1 PSTPIP1 trimer [cytosol] PSTPIP1 trimer Reactome DB_ID: 9787766 3 UniProt:P97814 Pstpip1 UniProt P97814 1 EQUAL 416 EQUAL Reactome Database ID Release 78 9787768 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787768 Reactome R-MMU-879213 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-879213.1 Reactome DB_ID: 9787749 1 Pyrin trimer [cytosol] Pyrin trimer Reactome DB_ID: 9787747 3 UniProt:Q9JJ26 Mefv UniProt Q9JJ26 1 EQUAL 781 EQUAL Reactome Database ID Release 78 9787749 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787749 Reactome R-MMU-879202 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-879202.1 Reactome DB_ID: 9787770 1 PSTPIP1 trimer:Pyrin trimer [cytosol] PSTPIP1 trimer:Pyrin trimer Reactome DB_ID: 9787768 1 Reactome DB_ID: 9787749 1 Reactome Database ID Release 78 9787770 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787770 Reactome R-MMU-879197 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-879197.1 Reactome Database ID Release 78 9787772 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787772 Reactome R-MMU-879221 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-879221.1 Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) is a pyrin-binding protein, involved in regulation of the actin cytoskeleton (Li et al. 1998) and suggested as a regulator of inflammasome activation (Khare et al. 2010). A naturally occurring mutation of PSTPIP1 where Y344 is replaced by F blocks tyrosine phosphorylation and reduces pyrin binding. Mutations of PSTPIP1 that increase pyrin binding are associated with the inflammatory syndrome pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA). Expression of PSTPIP1 with these mutations in THP-11 cells resulted in substantially increased caspase-1 activation and IL-1beta secretion. PSTPIP1 binding to pyrin is believed to promote the unmasking of its PYD domain and enhance interactions with ASC, facilitating ASC oligomerization and caspase-1 recruitment (Yu et al. 2007). 17964261 Pubmed 2007 Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants Yu, JW Fernandes-Alnemri, T Datta, P Wu, J Juliana, C Solorzano, L McCormick, M Zhang, Z Alnemri, ES Mol Cell 28:214-27 9857189 Pubmed 1998 A cdc15-like adaptor protein (CD2BP1) interacts with the CD2 cytoplasmic domain and regulates CD2-triggered adhesion Li, J Nishizawa, K An, W Hussey, RE Lialios, FE Salgia, R Sunder-Plassmann, R Reinherz, EL EMBO J 17:7320-36 21083527 Pubmed 2010 Inflammasomes and their activation Khare, S Luc, N Dorfleutner, A Stehlik, C Crit Rev Immunol 30:463-87 14595024 Pubmed 2003 Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway Shoham, NG Centola, M Mansfield, E Hull, KM Wood, G Wise, CA Kastner, DL Proc Natl Acad Sci U S A 100:13501-6 inferred by electronic annotation IEA GO IEA Pyrin binds ASC Pyrin binds ASC This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9787749 1 Reactome DB_ID: 9787752 3 UniProt:Q9EPB4 Pycard Pycard Asc Pycard FUNCTION Functions as key mediator in apoptosis and inflammation. Promotes caspase-mediated apoptosis involving predominantly caspase-8 and also caspase-9 in a probable cell type-specific manner. Involved in activation of the mitochondrial apoptotic pathway, promotes caspase-8-dependent proteolytic maturation of BID independently of FADD in certain cell types and also mediates mitochondrial translocation of BAX and activates BAX-dependent apoptosis coupled to activation of caspase-9, -2 and -3. Involved in macrophage pyroptosis, a caspase-1-dependent inflammatory form of cell death and is the major constituent of the ASC pyroptosome which forms upon potassium depletion and rapidly recruits and activates caspase-1. In innate immune response believed to act as an integral adapter in the assembly of the inflammasome which activates caspase-1 leading to processing and secretion of proinflammatory cytokines. The function as activating adapter in different types of inflammasomes is mediated by the pyrin and CARD domains and their homotypic interactions. Required for recruitment of caspase-1 to inflammasomes containing certain pattern recognition receptors, such as NLRP2, NLRP3, AIM2 and probably IFI16. In the NLRP1 and NLRC4 inflammasomes seems not be required but facilitates the processing of procaspase-1. In cooperation with NOD2 involved in an inflammasome activated by bacterial muramyl dipeptide leading to caspase-1 activation. May be involved in DDX58-triggered proinflammatory responses and inflammasome activation. In collaboration with AIM2 which detects cytosolic double-stranded DNA may also be involved in a caspase-1-independent cell death that involves caspase-8. In adaptive immunity may be involved in maturation of dendritic cells to stimulate T-cell immunity and in cytoskeletal rearrangements coupled to chemotaxis and antigen uptake may be involved in post-transcriptional regulation of the guanine nucleotide exchange factor DOCK2; the latter function is proposed to involve the nuclear form. Also involved in transcriptional activation of cytokines and chemokines independent of the inflammasome; this function may involve AP-1, NF-kappa-B, MAPK and caspase-8 signaling pathways. For regulation of NF-kappa-B activating and inhibiting functions have been reported. Modulates NF-kappa-B induction at the level of the IKK complex by inhibiting kinase activity of CHUK and IKBK. Proposed to compete with RIPK2 for association with CASP1 thereby down-regulating CASP1-mediated RIPK2-dependent NF-kappa-B activation and activating interleukin-1 beta processing. Modulates host resistance to DNA virus infection, probably by inducing the cleavage of and inactivating CGAS in presence of cytoplasmic double-stranded DNA (PubMed:28314590).SUBUNIT Self-associates; enforced oligomerization induces apoptosis, NF-kappa-B regulation and interleukin-1 beta secretion (By similarity). Homooligomers can form disk-like particles of approximately 12 nm diameter and approximately 1 nm height (By similarity). Component of several inflammasomes containing one pattern recognition receptor/sensor, such as NLRP2, NLRP3, NLRC4, AIM2, MEFV or NOD2, and probably NLRC4, NLRP12 or IFI16 (By similarity). Major component of the ASC pyroptosome, a 1-2 um supramolecular assembly (one per macrophage cell) which consists of oligomerized PYCARD dimers and CASP1 (By similarity). Interacts with CASP1 (precursor form); the interaction induces activation of CASP1 leading to the processing of interleukin-1 beta; PYCARD competes with RIPK2 for binding to CASP1 (By similarity). Interacts with NLRP3; the interaction requires the homooligomerization of NLRP3 (By similarity). Interacts with NLRP2, NLRC4, MEFV, CARD16, AIM2, IFI16, NOD2, DDX58, RIPK2, PYDC1, PYDC2, NLRP10, CHUK, IKBKB and BAX (By similarity). Interacts with CASP8 (PubMed:22555457).TISSUE SPECIFICITY Expressed in small intestine, colon, thymus, spleen, brain, heart, skeletal muscle, kidney, lung and liver.DEVELOPMENTAL STAGE Strongly expressed at 9.5 dpc in the telencephalon, thalamic areas of the diencephalon, heart and liver.DOMAIN The CARD domain mediates interaction with CASP1 and NLRC4.DOMAIN The pyrin domain mediates homotypic interactions with pyrin domains of proteins such as of NLRP3, PYDC1, PYDC2 and AIM2.PTM Phosphorylated.DISRUPTION PHENOTYPE Increased resistance to endotoxic shock and severe defects in caspase-1 activation and interleukin-1 beta and interleukin-18 production in macrophages in response to several pro-inflammatory molecules (PubMed:15190255, PubMed:15507117). Mutants are resitant to vaccinia virus (VACV) but not vesicular somatitis virus (VSV) infection. They show lower viral loads in the lungs compared to wild type mice, they produce higher levels of type I IFN, IL6 and RSAD2/Viperin after VCAV INFECTION (PubMed:28314590). UniProt Q9EPB4 1 EQUAL 195 EQUAL Reactome DB_ID: 9787754 1 Pyrin trimer:ASC [cytosol] Pyrin trimer:ASC Reactome DB_ID: 9787749 1 Reactome DB_ID: 9787752 3 1 EQUAL 195 EQUAL Reactome Database ID Release 78 9787754 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787754 Reactome R-MMU-877352 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-877352.1 Reactome Database ID Release 78 9787756 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787756 Reactome R-MMU-877361 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-877361.1 Trimeric pyrin interacts with ASC through its Pyrin domains, leading to oligomerization of ASC. This interaction interferes with the ability of NLRP3 (Cyropyrin) to associate with ASC and thus inhibits inflammasome activation (Chae et al. 2003). 12615073 Pubmed 2003 Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product Dowds, TA Masumoto, J Chen, FF Ogura, Y Inohara, N Nunez, G Biochem Biophys Res Commun 302:575-80 12667444 Pubmed 2003 Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis Chae, JJ Komarow, HD Cheng, J Wood, G Raben, N Liu, PP Kastner, DL Mol Cell 11:591-604 11498534 Pubmed 2001 Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis Richards, N Schaner, P Diaz, A Stuckey, J Shelden, E Wadhwa, A Gumucio, DL J Biol Chem 276:39320-9 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9861966 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861966 Reactome R-MMU-844456 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-844456.1 The NLRP3 (Cryopyrin) inflammasome is currently the best characterized. It consists of NLRP3, ASC (PYCARD) and procaspase-1; CARD8 (Cardinal) is also suggested to be a component. It is activated by a number of pathogens and bacterial toxins as well as diverse PAMPs, danger-associated molecular patterns (DAMPS) such as hyaluronan and uric acid, and exogenous irritants such as silica and asbestos (see Table S1 Schroder & Tschopp, 2010).<br> Mutations in NLRP3 which lead to constitutive activation are linked to the human diseases Muckle-Wells syndrome, familial cold autoinflammatory syndrome and NOMID (Ting et al. 2006), characterized by skin rashes and other symptoms associated with generalized inflammation. The cause of these symptoms is uncontrolled IL-1 beta production. Multiple studies have shown that activation of the NLRP3 inflammasome by particulate activators (e.g. Hornung et al. 2008) requires phagocytosis, but this is not required for the response to ATP, which is mediated by the P2X7 receptor (Kahlenberg & Dubyak, 2004) and appears to involve the pannexin membrane channel (Pellegrin & Suprenenant 2006). Direct binding of activators to NLRP3 has not been demonstrated and the exact process of activation is unclear, though it is speculated to involve changes in conformation that free the NACHT domain for oligomerization (Inohara & Nunez 2001, 2003). 16498449 Pubmed 2006 CATERPILLERs, pyrin and hereditary immunological disorders Ting, JP Kastner, DL Hoffman, HM Nat Rev Immunol 6:183-95 inferred by electronic annotation IEA GO IEA The NLRP1 inflammasome The NLRP1 inflammasome This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Bcl-2 and Bcl-XL bind NLRP1 Bcl-2 and Bcl-XL bind NLRP1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9787758 1 mitochondrial outer membrane GO 0005741 Bcl-2/Bcl-X(L) [mitochondrial outer membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Bcl2 [mitochondrial outer membrane] Bcl2l1 [mitochondrial outer membrane] UniProt P10417 UniProt Q64373 Reactome DB_ID: 9787561 1 UniProt:Q2LKU9 Nlrp1a UniProt Q2LKU9 1 EQUAL 1473 EQUAL Reactome DB_ID: 9787760 1 Bcl-2/Bcl-X(L):NLRP1 [mitochondrial outer membrane] Bcl-2/Bcl-X(L):NLRP1 Converted from EntitySet in Reactome Reactome DB_ID: 9787758 1 Reactome DB_ID: 9787561 1 1 EQUAL 1473 EQUAL Reactome Database ID Release 78 9787760 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787760 Reactome R-MMU-879218 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-879218.1 Reactome Database ID Release 78 9787762 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787762 Reactome R-MMU-879201 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-879201.1 The anti-apoptotic proteins Bcl-2 and Bcl-XL (but not Mcl-1, Bcl-W, Bfl-1 or Bcl-B) bind to NLRP1, preventing MDP-induced activation. 17418785 Pubmed 2007 Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1 Bruey, JM Bruey-Sedano, N Luciano, F Zhai, D Balpai, R Xu, C Kress, CL Bailly-Maitre, B Li, X Osterman, A Matsuzawa, S Terskikh, AV Faustin, B Reed, JC Cell 129:45-56 inferred by electronic annotation IEA GO IEA NLRP1 senses MDP NLRP1 senses MDP This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9787561 1 1 EQUAL 1473 EQUAL Reactome DB_ID: 708341 1 Reactome DB_ID: 9787563 1 MDP:NLRP1 [cytosol] MDP:NLRP1 Reactome DB_ID: 9787561 1 1 EQUAL 1473 EQUAL Reactome DB_ID: 708341 1 Reactome Database ID Release 78 9787563 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787563 Reactome R-MMU-877370 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-877370.1 Reactome Database ID Release 78 9787571 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787571 Reactome R-MMU-844447 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-844447.1 In vitro studies using purified NLRP1 and caspase-1 suggest that MDP induces a conformational change in NLRP1 that allows it to bind nucleotides and oligomerize, creating a binding platform for caspase-1 (Faustin et al. 2008). There is no direct evidence that NLRP1 binds MDP so the mechanism that stimulates NLRP1 is unclear. 17349957 Pubmed 2007 Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation Faustin, B Lartigue, L Bruey, JM Luciano, F Sergienko, E Bailly-Maitre, B Volkmann, N Hanein, D Rouiller, I Reed, JC Mol Cell 25:713-24 inferred by electronic annotation IEA GO IEA MDP:NLRP1 binds ATP MDP:NLRP1 binds ATP This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Reactome DB_ID: 9787563 1 Reactome DB_ID: 9787565 1 MDP:NLRP1:ATP [cytosol] MDP:NLRP1:ATP Reactome DB_ID: 113592 1 Reactome DB_ID: 9787563 1 Reactome Database ID Release 78 9787565 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787565 Reactome R-MMU-879207 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-879207.1 Reactome Database ID Release 78 9787774 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787774 Reactome R-MMU-879222 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-879222.1 MDP may induce a conformational change in NLRP1 which enables ATP binding, required for NLRP1 oligomerization (Faustin et al. 2007). inferred by electronic annotation IEA GO IEA NLRP1 oligomerizes NLRP1 oligomerizes This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9787565 1 Reactome DB_ID: 9787567 1 MDP:NLRP1:ATP oligomer [cytosol] MDP:NLRP1:ATP oligomer Reactome Database ID Release 78 9787569 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787569 Reactome R-MMU-844438 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-844438.1 NLRP1 in the presence of Mg2+ was seen to have altered electrophoretic mobility when MDP was added. This was interpreted as evidence of NLRP1 oligomerization. The extent of oligomerization is unknown. inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9861954 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861954 Reactome R-MMU-844455 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-844455.1 NLRP1 is activated by MDP (Faustin et al. 2007). The NLRP1 inflammasome was the first to be characterized. It was described as a complex containing NALP1, ASC, caspase-1 and caspase-5 (Martinon et al. 2002). Unlike NLRP3, NLRP1 has a C-terminal extension containing a CARD domain, which has been reported to interact directly with procaspase-1, obviating a requirement for ASC (Faustin et al. 2007), though ASC was found to augment the interaction. Mouse NLRP1 has no PYD domain and would therefore not be expected to interact directly with procaspase-1. Like the NLRP3 inflammasome, K+ efflux appears to be essential for caspase-1 activation (Wickliffe et al. 2008). Ribonucleoside triphosphates (NTPs) are required for NALP1-mediated caspase-1 activation with ATP being the most efficient, Mg2+ was also required (Faustin et al. 2007). The human NLRP1 gene has 3 paralogues in mouse that are highly polymorphic. Differences between mouse strains underlie susceptibility to anthrax lethal toxin (Boyden & Dietrich 2006). 12191486 Pubmed 2002 The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta Martinon, F Burns, K Tschopp, Jürg Mol Cell 10:417-26 16429160 Pubmed 2006 Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin Boyden, ED Dietrich, WF Nat Genet 38:240-4 17850338 Pubmed 2008 Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome Wickliffe, KE Leppla, Stephen H Moayeri, Mahtab Cell Microbiol 10:332-43 inferred by electronic annotation IEA GO IEA The AIM2 inflammasome The AIM2 inflammasome This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> AIM2 binds dsDNA AIM2 binds dsDNA This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 874088 1 deoxyribonucleic acid [ChEBI:16991] deoxyribonucleic acid Desoxyribonukleinsaeure (Deoxyribonucleotide)n+m (Deoxyribonucleotide)m thymus nucleic acid DNA deoxyribonucleic acids DNAn DNS desoxyribose nucleic acid (Deoxyribonucleotide)n DNAn+1 ChEBI 16991 Reactome DB_ID: 9787574 1 UniProt:Q91VJ1 Aim2 Aim2 Aim2 Gm1313 Ifi210 FUNCTION Involved in innate immune response by recognizing cytosolic double-stranded DNA and inducing caspase-1-activating inflammasome formation in macrophages. Upon binding to DNA is thought to undergo oligomerization and to associate with PYCARD initiating the recruitment of caspase-1 precusrsor and processing of interleukin-1 beta and interleukin-18. Detects cytosolic dsDNA of viral and bacterial origin in a non-sequence-specific manner. Can also trigger PYCARD-dependent, caspase-1-independent cell death that involves caspase-8.ACTIVITY REGULATION In absence of dsDNA pyrin and HIN-20 domain can interact inducing a closed conformation; an autoinhibitory mechanism is proposed in which binding to dsDNA liberates the pyrin domain for homotypic downstream signaling interactions with PYCARD.SUBUNIT Self-associates; forms homooligomers in response to cytosolic dsDNA and the dsDNA seems to serve as oligomerization platform. Component of the AIM2 inflammasome complex. Interacts with PYCARD. Interacts with IFI16 (By similarity). Interacts with EIF2AK2/PKR (By similarity). Interacts with PYDC5; disrupts assembly of the ALR inflammasome complex (By similarity).DOMAIN The HIN-20 domain mediates dsDNA binding via electrostatic interactions.DOMAIN The pyrin domain mediates homotypic interaction with PYCARD.SIMILARITY Belongs to the HIN-200 family. UniProt Q91VJ1 1 EQUAL 343 EQUAL Reactome DB_ID: 9787576 1 dsDNA:AIM2 [cytosol] dsDNA:AIM2 Reactome DB_ID: 874088 1 Reactome DB_ID: 9787574 1 1 EQUAL 343 EQUAL Reactome Database ID Release 78 9787576 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787576 Reactome R-MMU-874096 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-874096.1 Reactome Database ID Release 78 9787578 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9787578 Reactome R-MMU-844619 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-844619.1 AIM2 binds to cytosolic dsDNA via its C-terminal HIN domain. The source of the dsDNA can be can be viral, bacterial or derived from the host (Hornung et al. 2009, Muruve et al. 2008). Multiple AIM2 molecules may bind the same dsDNA (Fernandes-Alnemri et al. 2008). 19158676 Pubmed 2009 AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA Fernandes-Alnemri, T Yu, JW Datta, P Wu, J Alnemri, ES Nature 458:509-13 19158675 Pubmed 2009 AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC Hornung, V Ablasser, A Charrel-Dennis, M Bauernfeind, FG Horvath, G Caffrey, DR Latz, E Fitzgerald, Katherine A Nature 458:514-8 19158679 Pubmed 2009 An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome Burckstummer, Tilmann Baumann, C Bluml, Stephan Dixit, E Durnberger, Gerhard Jahn, H Planyavsky, M Bilban, M Colinge, J Bennett, KL Superti-Furga, G Nat Immunol 10:266-72 18288107 Pubmed 2008 The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response Muruve, DA Pétrilli, V Zaiss, AK White, LR Clark, SA Ross, PJ Parks, RJ Tschopp, Jürg Nature 452:103-7 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9861958 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861958 Reactome R-MMU-844615 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-844615.1 AIM2 is a member of the PYHIN or HIN200 family. It has a C-terminal HIN domain which can bind double-stranded DNA (dsDNA) and a PYD domain that can bind ASC via a PYD-PYD interaction. In cells expressing procaspase-1, The interaction of AIM2 with ASC leads to recruitment of procaspase-1 forming the ASC pyroptosome which induces pyroptotic cell death by generating active caspase-1. Data from AIM2 deficient mice indicates that the AIM2 inflammasome is a nonredundant sensor for dsDNA that regulates the caspase-1-dependent maturation of IL-1beta and IL-18 (Rathinam et al. 2010, Hornung & Latz, 2009). 20351692 Pubmed 2010 The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses Rathinam, VA Jiang, Z Waggoner, SN Sharma, S Cole, LE Waggoner, L Vanaja, SK Monks, BG Ganesan, S Latz, E Hornung, V Vogel, SN Szomolanyi-Tsuda, E Fitzgerald, Katherine A Nat Immunol 11:395-402 20098460 Pubmed 2010 Intracellular DNA recognition Hornung, V Latz, E Nat Rev Immunol 10:123-30 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9861956 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861956 Reactome R-MMU-622312 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-622312.1 In contrast to NOD1/2 some NLRPs function as large macromolecular complexes called 'Inflammasomes'. These multiprotein platforms control activation of the cysteinyl aspartate protease caspase-1 and thereby the subsequent cleavage of pro-interleukin 1B (pro-IL1B) into the active proinflammatory cytokine IL1B. Activation of caspase-1 is essential for production of IL1B and IL18, which respectively bind and activate the IL1 receptor (IL1R) and IL18 receptor (IL18R) complexes. IL1R and IL18R activate NFkappaB and other signaling cascades.<br><br>As the activation of inflammasomes leads to caspase-1 activation, inflammasomes can be considered an upstream step of the IL1R and IL18R signaling cascades, linking intracellular pathogen sensing to immune response pathways mediated by Toll-Like Receptors (TLRs). Monocytes and macrophages do not express pro-IL1B until stimulated, typically by TLRs (Franchi et al. 2009). The resulting pro-IL1B is not converted to IL1B unless a second stimulus activates an inflammasome. This requirement for two distinct stimuli allows tight regulation of IL1B/IL18 production, necessary because excessive IL-1B production is associated with numerous inflammatory diseases such as gout and rheumatoid arthritis (Masters et al. 2009).<br><br>There are at least four subtypes of the inflammasome, characterized by the NLRP. In addition the protein AIM2 can form an inflammasome. All activate caspase-1. NLRP1 (NALP1), NLRP3 (Cryopyrin, NALP3), IPAF (CARD12, NLRC4) and AIM2 inflammasomes all have clear physiological roles in vivo. NLRP2, NLRP6, NLRP7, NLRP10 and NLRP12 have been demonstrated to modulate caspase-1 activity in vitro but the significance of this is unclear (Mariathasan and Monack, 2007).<br><br>NLRP3 and AIM2 bind the protein 'apoptosis-associated speck-like protein containing a CARD' (ASC, also called PYCARD), via a PYD-PYD domain interaction. This in turn recruits procaspase-1 through a CARD-CARD interaction. NLRP1 and IPAF contain CARD domains and can bind procaspase-1 directly, though both are stimulated by ASC. Oligomerization of NLRPs is believed to bring procaspases into close proximity, leading to 'induced proximity' auto-activation (Boatright et al. 2003). This leads to formation of the active caspase tetramer. NLRPs are generally considered to be cytoplasmic proteins, but there is evidence for cytoplasmic-nuclear shuttling of the family member CIITA (LeibundGut-Landmann et al. 2004) and tissue/cell dependent NALP1 expression in the nucleus of neurons and lymphocytes (Kummer et al. 2007); the significance of this remains unclear. 19302049 Pubmed 2009 Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*) Masters, SL Simon, A Aksentijevich, I Kastner, DL Annu Rev Immunol 27:621-68 12620239 Pubmed 2003 A unified model for apical caspase activation Boatright, KM Renatus, M Scott, FL Sperandio, S Shin, H Pedersen, IM Ricci, JE Edris, WA Sutherlin, DP Green, DR Salvesen, Guy S. Mol Cell 11:529-41 15162420 Pubmed 2004 Mini-review: Specificity and expression of CIITA, the master regulator of MHC class II genes LeibundGut-Landmann, S Waldburger, JM Krawczyk, M Otten, LA Suter, T Fontana, A Acha-Orbea, Hans Reith, W Eur J Immunol 34:1513-25 19120479 Pubmed 2009 Inflammasomes: guardians of cytosolic sanctity Lamkanfi, M Dixit, VM Immunol Rev 227:95-105 17186029 Pubmed 2007 Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation Mariathasan, S Monack, DM Nat Rev Immunol 7:31-40 17164409 Pubmed 2007 Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response Kummer, JA Broekhuizen, R Everett, H Agostini, L Kuijk, L Martinon, F Van Bruggen, R Tschopp, Jürg J Histochem Cytochem 55:443-52 19120480 Pubmed 2009 Function of Nod-like receptors in microbial recognition and host defense Franchi, L Warner, N Viani, K Nunez, G Immunol Rev 227:106-28 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9860876 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860876 Reactome R-MMU-168643 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-168643.1 GO 0035872 GO biological process The innate immune system is the first line of defense against invading microorganisms, a broad specificity response characterized by the recruitment and activation of phagocytes and the release of anti-bacterial peptides. The receptors involved recognize conserved molecules present in microbes called pathogen-associated molecular patterns (PAMPs), and/or molecules that are produced as a result of tissue injury, the damage associated molecular pattern molecules (DAMPs). PAMPs are essential to the pathogen and therefore unlikely to vary. Examples are lipopolysaccharide (LPS), peptidoglycans (PGNs) and viral RNA. DAMPs include intracellular proteins, such as heat-shock proteins and extracellular matrix proteins released by tissue injury, such as hyaluronan fragments. Non-protein DAMPs include ATP, uric acid, heparin sulfate and dsDNA. The receptors for these factors are referred to collectively as pathogen- or pattern-recognition receptors (PRRs). The best studied of these are the membrane-associated Toll-like receptor family. Less well studied but more numerous are the intracellular nucleotide-binding domain, leucine rich repeat containing receptors (NLRs) also called nucleotide binding oligomerization domain (NOD)-like receptors, a family with over 20 members in humans and over 30 in mice. These recognise PAMPs/DAMPs from phagocytosed microorganisms or from intracellular infections (Kobayashi et al. 2003, Proell et al. 2008, Wilmanski et al. 2008). Some NLRs are involved in process unrelated to pathogen detection such as tissue homeostasis, apoptosis, graft-versus-host disease and early development (Kufer & Sansonetti 2011). <br><br><br>Structurally NLRs can be subdivided into the caspase-recruitment domain (CARD)-containing NLRCs (NODs) and the pyrin domain (PYD)-containing NLRPs (NALPs), plus outliers including ice protease (caspase-1) activating factor (IPAF) (Martinon & Tschopp, 2005). In practical terms, NLRs can be divided into the relatively well characterized NOD1/2 which signal via RIP2 primarily to NFkappaB, and the remainder, some of which participate in macromolecular structures called Inflammasomes that activate caspases. Mutations in several members of the NLR protein family have been linked to inflammatory diseases, suggesting these molecules play important roles in maintaining host-pathogen interactions and inflammatory responses.<br><br><br>Most NLRs have a tripartite structure consisting of a variable amino-terminal domain, a central nucleotide-binding oligomerization domain (NOD or NACHT) that is believed to mediate the formation of self oligomers, and a carboxy-terminal leucine-rich repeat (LRR) that detects PAMPs/DAMPs. In most cases the amino-terminal domain includes protein-interaction modules, such as CARD or PYD, some harbour baculovirus inhibitor repeat (BIR) or other domains. For most characterised NLRs these domains have been attributed to downstream signaling<br><br>Under resting conditions, NLRs are thought to be present in an autorepressed form, with the LRR folded back onto the NACHT domain preventing oligomerization. Accessory proteins may help maintain the inactive state. PAMP/DAMP exposure is thought to triggers conformational changes that expose the NACHT domain enabling oligomerization and recruitment of effectors, though it should be noted that due to the lack of availability of structural data, the mechanistic details of NLR activation remain largely elusive.<br><br>New terminology for NOD-like receptors was adopted by the Human Genome Organization (HUGO) in 2008 to standardize the nomenclature of NLRs. The acronym NLR, once standing for NOD-like receptor, now is an abbreviation of 'nucleotide-binding domain, leucine-rich repeat containing' protein. The term NOD-like receptor is officially outdated and replaced by NLRC where the C refers to the CARD domain. However the official gene symbols for NOD1 and NOD2 still contain NOD and this general term is still widely used. 12830145 Pubmed 2003 Intracellular debugging Kobayashi, KS Eynon, EE Flavell, RA Nat Immunol 4:652-4 21245903 Pubmed 2011 NLR functions beyond pathogen recognition Kufer, TA Sansonetti, PJ Nat Immunol 12:121-8 18446235 Pubmed 2008 The Nod-like receptor (NLR) family: a tale of similarities and differences Proell, M Riedl, SJ Fritz, JH Rojas, AM Schwarzenbacher, R PLoS One 3:e2119 17875812 Pubmed 2008 NLR proteins: integral members of innate immunity and mediators of inflammatory diseases Wilmanski, JM Petnicki-Ocwieja, T Kobayashi, KS J Leukoc Biol 83:13-30 inferred by electronic annotation IEA GO IEA