BioPAX pathway converted from "Inflammasomes" in the Reactome database.InflammasomesInflammasomesIn 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. Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28The NLRP3 inflammasomeThe NLRP3 inflammasomeThe 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).Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28ATP binds to P2X7ATP binds to P2X7P2X7 is a receptor for extracellular ATP that acts as a ligand gated non-selective cation channel. It is also responsible for the ATP-dependent lysis of macrophages, which it brings about by mediating the formation of membrane pores permeable to large molecules (Adinolfi et al. 2005).Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 8772151plasma membraneGO0005886UniProt:Q99572 P2RX7P2RX7P2RX7FUNCTION Receptor for ATP that acts as a ligand-gated ion channel. Responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to large molecules. Could function in both fast synaptic transmission and the ATP-mediated lysis of antigen-presenting cells. In the absence of its natural ligand, ATP, functions as a scavenger receptor in the recognition and engulfment of apoptotic cells (PubMed:21821797, PubMed:23303206).SUBUNIT Functional P2XRs are organized as homomeric and heteromeric trimers. Interacts with LAMA3, ITGB2, ACTB, ACTN4, SVIL, MPP3, HSPA1, HSPCB, HSPA8, PIK230 and PTPRB. Interacts (via C-terminus) with EMP2 (PubMed:12107182).TISSUE SPECIFICITY Widely expressed with highest levels in brain and immune tissues.PTM Phosphorylation results in its inactivation.PTM ADP-ribosylation at Arg-125 is necessary and sufficient to activate P2RX7 and gate the channel.PTM Palmitoylation of several cysteines in the C-terminal cytoplasmic tail is required for efficient localization to cell surface.SIMILARITY Belongs to the P2X receptor family.Reactomehttp://www.reactome.orgHomo sapiensNCBI Taxonomy9606UniProtQ99572Chain Coordinates1EQUAL595EQUALReactome DB_ID: 1145701extracellular regionGO0005576ATP(4-) [ChEBI:30616]ATP(4-)Adenosine 5'-triphosphateatpATPChEBI30616Reactome DB_ID: 8771661ATP:P2X7 [plasma membrane]ATP:P2X7Reactome DB_ID: 87721511EQUAL595EQUALReactome DB_ID: 1145701Reactome Database ID Release 75877166Database 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=877166ReactomeR-HSA-8771661Reactome 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-HSA-877166.1Reactome Database ID Release 75877178Database 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=877178ReactomeR-HSA-8771781Reactome 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-HSA-877178.118404507Pubmed2005P2X(7) receptor: Death or life?Adinolfi, EPizzirani, CIdzko, MPanther, ENorgauer, JDi Virgilio, FFerrari, DPurinergic Signal 1:219-27P2X7 forms oligomeric non-selective cation channelsP2X7 forms oligomeric non-selective cation channelsAt low to intermediate concentrations of extracellular ATP, P2X4 and P2X7 probably function as heterotrimeric, reversible ATP-gated, non-desensitizing cation channels (Markwardt 2007).Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 8771663Reactome DB_ID: 8772571ATP:P2X7 oligomer [plasma membrane]ATP:P2X7 oligomerReactome DB_ID: 8771663Reactome Database ID Release 75877257Database 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=877257ReactomeR-HSA-8772571Reactome 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-HSA-877257.1Reactome Database ID Release 75877158Database 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=877158ReactomeR-HSA-8771581Reactome 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-HSA-877158.118404439Pubmed2007Activation kinetics of single P2X receptorsMarkwardt, FPurinergic Signal 3:249-253P2X7 mediates loss of intracellular K+P2X7 mediates loss of intracellular K+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). Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 298041cytosolGO0005829potassium(1+) [ChEBI:29103]potassium(1+)K+PotassiumChEBI29103Reactome DB_ID: 741261PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 877257GO0004931GO molecular functionReactome Database ID Release 75877259Database 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=877259Reactome Database ID Release 75877187Database 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=877187ReactomeR-HSA-8771871Reactome 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-HSA-877187.111157473Pubmed2001Nucleotide receptors: an emerging family of regulatory molecules in blood cellsDi Virgilio, FChiozzi, PFerrari, DFalzoni, SSanz, JMMorelli, ATorboli, MBolognesi, GBaricordi, ORBlood 97:587-6009023774Pubmed1997Purinoceptor-operated cationic channels in human B lymphocytesMarkwardt, FLohn, MatthiasBohm, ThomasKlapperstuck, MJ Physiol 498:143-51P2X7 mediates membrane pores that include pannexin-1P2X7 mediates membrane pores that include pannexin-1At 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).Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 8772571Reactome DB_ID: 3753441UniProt:Q96RD7 PANX1PANX1PANX1MRS1UNQ2529/PRO6028FUNCTION Structural component of the gap junctions and the hemichannels involved in the ATP release and nucleotide permeation (PubMed:16908669, PubMed:20829356, PubMed:30918116). May play a role as a Ca(2+)-leak channel to regulate ER Ca(2+) homeostasis (PubMed:16908669). Plays a critical role in oogenesis (PubMed:30918116).SUBUNIT Homohexamer. Forms homomeric or PANX1/PANX2-heteromeric intercellular channels on coexpression in paired Xenopus oocytes (By similarity).TISSUE SPECIFICITY Widely expressed (PubMed:30918116). Highest expression is observed in oocytes and brain (PubMed:30918116). Detected at very low levels in sperm cells (PubMed:30918116).PTM S-nitrosylation inhibits channel currents and ATP release.PTM N-glycosylation may play a role in cell surface targeting (By similarity). Exists in three glycosylation states: non-glycosylated (GLY0), high-mannose glycosylated (GLY1), and fully mature glycosylated (GLY2) (PubMed:30918116).SIMILARITY Belongs to the pannexin family.UniProtQ96RD71EQUAL426EQUALReactome DB_ID: 8772421ATP:P2X7 oligomer:Pannexin-1 [plasma membrane]ATP:P2X7 oligomer:Pannexin-1Reactome DB_ID: 8772571Reactome DB_ID: 37534411EQUAL426EQUALReactome Database ID Release 75877242Database 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=877242ReactomeR-HSA-8772421Reactome 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-HSA-877242.1Reactome Database ID Release 75877198Database 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=877198ReactomeR-HSA-8771981Reactome 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-HSA-877198.1450099Pubmed1979ATP induces nucleotide permeability in rat mast cellsCockcroft, SGomperts, BDNature 279:541-217240370Pubmed2007Pannexin1 is part of the pore forming unit of the P2X(7) receptor death complexLocovei, SScemes, EQiu, FSpray, DCDahl, GFEBS Lett 581:483-817036048Pubmed2006Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptorPelegrin, PSurprenant, AEMBO J 25:5071-8214597722Pubmed2003Pannexins, a family of gap junction proteins expressed in brainBruzzone, RHormuzdi, SGBarbe, MTHerb, AMonyer, HProc Natl Acad Sci U S A 100:13644-93597398Pubmed1987ATP4- permeabilizes the plasma membrane of mouse macrophages to fluorescent dyesSteinberg, THNewman, ASSwanson, JASilverstein, SCJ Biol Chem 262:8884-815715654Pubmed2005Pharmacological properties of homomeric and heteromeric pannexin hemichannels expressed in Xenopus oocytesBruzzone, RBarbe, MTJakob, NJMonyer, HJ Neurochem 92:1033-432182768Pubmed1990ATP-induced pore formation in the plasma membrane of rat peritoneal mast cellsTatham, PELindau, MJ Gen Physiol 95:459-7611707406Pubmed2001Proteomic and functional evidence for a P2X7 receptor signalling complexKim, MJiang, LHWilson, HLNorth, RASurprenant, AEMBO J 20:6347-5815075209Pubmed2004Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ releaseKahlenberg, JMDubyak, GRAm J Physiol Cell Physiol 286:C1100-815896293Pubmed2005Identification and characterization of splice variants of the human P2X7 ATP channelCheewatrakoolpong, BGilchrest, HAnthes, JCGreenfeder, SBiochem Biophys Res Commun 332:17-27SGT1 binds HSP90SGT1 binds HSP90The 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).Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 4196171UniProt:P08238 HSP90AB1HSP90AB1HSP90AB1HSP90BHSPC2HSPCBFUNCTION Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function (PubMed:16478993, PubMed:19696785). Engages with a range of client protein classes via its interaction with various co-chaperone proteins or complexes, that act as adapters, simultaneously able to interact with the specific client and the central chaperone itself. Recruitment of ATP and co-chaperone followed by client protein forms a functional chaperone. After the completion of the chaperoning process, properly folded client protein and co-chaperone leave HSP90 in an ADP-bound partially open conformation and finally, ADP is released from HSP90 which acquires an open conformation for the next cycle (PubMed:27295069, PubMed:26991466). Apart from its chaperone activity, it also plays a role in the regulation of the transcription machinery. HSP90 and its co-chaperones modulate transcription at least at three different levels. They first alter the steady-state levels of certain transcription factors in response to various physiological cues. Second, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and thereby respond to the change in the environment. Third, they participate in the eviction of histones from the promoter region of certain genes and thereby turn on gene expression (PubMed:25973397). Antagonizes STUB1-mediated inhibition of TGF-beta signaling via inhibition of STUB1-mediated SMAD3 ubiquitination and degradation (PubMed:24613385). Promotes cell differentiation by chaperoning BIRC2 and thereby protecting from auto-ubiquitination and degradation by the proteasomal machinery (PubMed:18239673). Main chaperone involved in the phosphorylation/activation of the STAT1 by chaperoning both JAK2 and PRKCE under heat shock and in turn, activates its own transcription (PubMed:20353823). Involved in the translocation into ERGIC (endoplasmic reticulum-Golgi intermediate compartment) of leaderless cargos (lacking the secretion signal sequence) such as the interleukin 1/IL-1; the translocation process is mediated by the cargo receptor TMED10 (PubMed:32272059).ACTIVITY REGULATION In the resting state, through the dimerization of its C-terminal domain, HSP90 forms a homodimer which is defined as the open conformation. Upon ATP-binding, the N-terminal domain undergoes significant conformational changes and comes in contact to form an active closed conformation. After HSP90 finishes its chaperoning tasks of assisting the proper folding, stabilization and activation of client proteins under the active state, ATP molecule is hydrolyzed to ADP which then dissociates from HSP90 and directs the protein back to the resting state.SUBUNIT Monomer (PubMed:24880080). Homodimer (PubMed:7588731, PubMed:18400751). Forms a complex with CDK6 and CDC37 (PubMed:9482106, PubMed:25486457). Interacts with UNC45A; binding to UNC45A involves 2 UNC45A monomers per HSP90AB1 dimer (PubMed:16478993). Interacts with CHORDC1 (By similarity). Interacts with DNAJC7 (PubMed:18620420). Interacts with FKBP4 (PubMed:15159550). May interact with NWD1 (PubMed:24681825). Interacts with SGTA (PubMed:16580629). Interacts with HSF1 in an ATP-dependent manner. Interacts with MET; the interaction suppresses MET kinase activity. Interacts with ERBB2 in an ATP-dependent manner; the interaction suppresses ERBB2 kinase activity. Interacts with HIF1A, KEAP1 and RHOBTB2 (PubMed:26517842). Interacts with STUB1 and SMAD3 (PubMed:24613385). Interacts with XPO1 and AHSA1 (PubMed:22022502, PubMed:25486457). Interacts with BIRC2 (PubMed:25486457). Interacts with KCNQ4; promotes cell surface expression of KCNQ4 (PubMed:23431407). Interacts with BIRC2; prevents auto-ubiquitination and degradation of its client protein BIRC2 (PubMed:18239673). Interacts with NOS3 (PubMed:23585225). Interacts with AHR; interaction is inhibited by HSP90AB1 phosphorylation on Ser-226 and Ser-255 (PubMed:15581363). Interacts with STIP1 and CDC37; upon SMYD2-dependent methylation (PubMed:24880080). Interacts with JAK2 and PRKCE; promotes functional activation in a heat shock-dependent manner (PubMed:20353823). Interacts with HSP90AA1; interaction is constitutive (PubMed:20353823). HSP90AB1-CDC37 chaperone complex interacts with inactive MAPK7 (via N-terminal half) in resting cells; the interaction is MAP2K5-independent and prevents from ubiquitination and proteasomal degradation (PubMed:23428871). Interacts with CDC25A; prevents heat shock-mediated CDC25A degradation and contributes to cell cycle progression (PubMed:22843495). Interacts with TP53 (via DNA binding domain); suppresses TP53 aggregation and prevents from irreversible thermal inactivation (PubMed:15358771). Interacts with TGFB1 processed form (LAP); inhibits latent TGFB1 activation (PubMed:20599762). Interacts with TRIM8; prevents nucleus translocation of phosphorylated STAT3 and HSP90AB1 (By similarity). Interacts with NR3C1 (via domain NR LBD) and NR1D1 (via domain NR LBD) (By similarity). Interacts with PDCL3 (By similarity). Interacts with TTC4 (via TPR repeats) (PubMed:18320024). Interacts with IL1B; the interaction facilitates cargo translocation into the ERGIC (PubMed:32272059).INDUCTION By heat shock.DOMAIN The TPR repeat-binding motif mediates interaction with TPR repeat-containing proteins.PTM Ubiquitinated in the presence of STUB1-UBE2D1 complex (in vitro).PTM ISGylated.PTM S-nitrosylated; negatively regulates the ATPase activity.PTM Phosphorylation at Tyr-301 by SRC is induced by lipopolysaccharide (PubMed:23585225). Phosphorylation at Ser-226 and Ser-255 inhibits AHR interaction (PubMed:15581363).PTM Methylated by SMYD2; facilitates dimerization and chaperone complex formation; promotes cancer cell proliferation.PTM Cleaved following oxidative stress resulting in HSP90AB1 protein radicals formation; disrupts the chaperoning function and the degradation of its client proteins.SIMILARITY Belongs to the heat shock protein 90 family.UniProtP082382EQUAL724EQUALReactome DB_ID: 8741071UniProt:Q9Y2Z0 SUGT1SUGT1SUGT1FUNCTION May play a role in ubiquitination and subsequent proteasomal degradation of target proteins.SUBUNIT Probably associates with SCF (SKP1-CUL1-F-box protein) complex through interaction with SKP1. Interacts with S100A6. Interacts with HSP90.DOMAIN The CS domain mediates interaction with HSP90.PTM Phosphorylated at Ser-281 and Ser-331, dephosphorylation promotes nuclear translocation, most likely due to disruption of the SUGT1-HSP90 complex.SIMILARITY Belongs to the SGT1 family.UniProtQ9Y2Z02EQUAL365EQUALReactome DB_ID: 8741121SUGT1:HSP90 [cytosol]SUGT1:HSP90Reactome DB_ID: 41961712EQUAL724EQUALReactome DB_ID: 87410712EQUAL365EQUALReactome Database ID Release 75874112Database 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=874112ReactomeR-HSA-8741121Reactome 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-HSA-874112.1Reactome Database ID Release 75874087Database 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=874087ReactomeR-HSA-8740872Reactome 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-HSA-874087.214761955Pubmed2004Human Sgt1 binds HSP90 through the CHORD-Sgt1 domain and not the tetratricopeptide repeat domainLee, YTJacob, JMichowski, WNowotny, MKuznicki, JChazin, WJJ Biol Chem 279:16511-7SGT1:HSP90 binds inactive NLRP3SGT1:HSP90 binds inactive NLRP3SGT1 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). Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 8741121Reactome DB_ID: 5611891UniProt:Q96P20 NLRP3NLRP3NALP3NLRP3C1orf7PYPAF1CIAS1FUNCTION 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 (and possibly CASP4 and CASP5). Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu (PubMed:28847925). 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 (PubMed:23871209). 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 (By similarity). 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 (By similarity).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 DAPIN/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 (PubMed:24630722). NLRP3 localizes at the end of each PYCARD filament (PubMed:24630722). Clustered PYCARD nucleates the formation of CASP1 filaments through the interaction of their respective CARD domains, acting as a platform for CASP1 polymerization (PubMed:24630722). 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 (PubMed:24630722). 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 (PubMed:24630722). Interacts with MEFV; this interaction targets NLRP3 to degradation by autophagy, hence preventing excessive IL1B- and IL18-mediated inflammation (PubMed:17431422) (PubMed:26347139). Interacts with GBP5 (via DAPIN domain); this interaction promotes inflammasome assembly in response to microbial and soluble, but not crystalline, agents (PubMed:22461501). 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 leucine-rich repeat (LRR) domain); PML-mediated increase in NLRP3 inflammasome activation does not depend upon this interaction (PubMed:23430110). Directly interacts with IRF4 (via the LRR domain); this interaction is required for optimal IRF4 binding to IL4 promoter and efficient IL4 transactivation during differentiation of Th2 helper T-cells (By similarity). Interacts (via NACHT domain) with DHX33 (via DEAH box) (PubMed:23871209). Interacts with PYDC5 (PubMed:24531343). Interacts (via NACHT domain) with DDX3X under both LPS-primed and inflammasome-activating conditions (By similarity) Interacts (via NACHT and LRR domains) with ARRB2; this interaction is direct and inducible by polyunsaturated fatty acids (PUFAs).TISSUE SPECIFICITY Predominantly expressed in macrophages. Also expressed in dendritic cells, B- and T-cells (at protein level) (PubMed:11786556) (PubMed:17164409). Expressed in LPS-treated granulocytes, but not in resting cells (at protein level) (PubMed:17164409). Expression in monocytes is very weak (at protein level) (PubMed:17164409). Expressed in stratified non-keratinizing squamous epithelium, including oral, esophageal and ectocervical mucosa and in the Hassall's corpuscles in the thymus. Also, detected in the stratified epithelium covering the bladder and ureter (transitional mucosa) (at protein level) (PubMed:17164409). Expressed in lung epithelial cells (at protein level) (PubMed:23229815). Expressed in chondrocytes (PubMed:12032915). Expressed at low levels in resting osteoblasts (PubMed:17907925).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), and by TNF (PubMed:14662828). Up-regulated in osteoblasts after exposure to invasive, but not invasion-defective, strains of Salmonella typhimurium (at protein level) (PubMed:17907925). In macrophages, up-regulated by endocannabinoid anandamide/AEA (PubMed:23955712).DOMAIN The pyrin domain (also called DAPIN domain or PYD) is involved in PYCARD-binding.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.PTM The disulfide bond in the pyrin domain might play a role in reactive oxygen species-mediated activation.PTM Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. Ubiquitination does not lead to degradation, but inhibits inflammasome activation (By similarity). 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.SIMILARITY Belongs to the NLRP family.UniProtQ96P201EQUAL1036EQUALReactome DB_ID: 8740861NLRP3:SUGT1:HSP90 [cytosol]NLRP3:SUGT1:HSP90Reactome DB_ID: 8741121Reactome DB_ID: 56118911EQUAL1036EQUALReactome Database ID Release 75874086Database 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=874086ReactomeR-HSA-8740861Reactome 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-HSA-874086.1Reactome Database ID Release 75873951Database 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=873951ReactomeR-HSA-8739513Reactome 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-HSA-873951.329712950Pubmed2018Hsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasomePiippo, NiinaKorhonen, EveliinaHytti, MariaSkottman, HKinnunen, KatiJosifovska, NatashaPetrovski, GoranKaarniranta, KaiKauppinen, AnuSci Rep 8:672017435760Pubmed2007A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responsesMayor, AMartinon, FDe Smedt, TPétrilli, VTschopp, JürgNat Immunol 8:497-503TXNIP binds reduced thioredoxinTXNIP binds reduced thioredoxinTXNIP 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).Authored: Jupe, S, 2011-04-15Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 12502461UniProt:Q9H3M7 TXNIPTXNIPVDUP1TXNIPFUNCTION 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. 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. Inhibits the proteasomal degradation of DDIT4, and thereby contributes to the inhibition of the mammalian target of rapamycin complex 1 (mTORC1).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.INDUCTION By 1,25-dihydroxyvitamin D-3 and TGFB1. Down-regulated in response to oxidative stress.PTM Ubiquitinated; undergoes polyubiquitination catalyzed by ITCH resulting in proteasomal degradation.SIMILARITY Belongs to the arrestin family.UniProtQ9H3M71EQUAL391EQUALReactome DB_ID: 660001UniProt:P10599 TXNTXNTRX1TRDXTXNTRXFUNCTION Participates in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyzes dithiol-disulfide exchange reactions (PubMed:2176490, PubMed:17182577, PubMed:19032234). 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 (PubMed:16408020, PubMed:17606900). 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 (PubMed:9108029, PubMed:11118054).FUNCTION ADF augments the expression of the interleukin-2 receptor TAC (IL2R/P55).SUBUNIT Homodimer; disulfide-linked (PubMed:9369469, PubMed:17260951). Interacts with TXNIP through the redox-active site (PubMed:17260951). Interacts with MAP3K5 and CASP3 (PubMed:15246877). In case of infection, interacts with S.typhimurium protein slrP (PubMed:19690162). Interacts with APEX1; the interaction stimulates the FOS/JUN AP-1 DNA-binding activity in a redox-dependent manner (PubMed:9108029).INDUCTION Up-regulated by ionizing radiation.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.PTM In case of infection, ubiquitinated by S.typhimurium protein slrP, leading to its degradation.ALLERGEN Causes an allergic reaction in human (PubMed:17182577, PubMed:19032234, PubMed:21489611). Recombinant protein binds to IgE in atopic eczema-suffering patients allergic to opportunistic skin-colonizing yeast M.sympodialis. Intermediate cross-reactivity is detected between the recombinant thioredoxin from M.sympodialis (Mala s 13) and recombinant form of this protein. Skin-prick test (SPT) and atopy patch test (APT) with 5 patients confirm cross-reactivity between the two proteins (PubMed:17182577). Recombinant protein binds to IgE of patients suffering from allergic bronchopulmonary aspergillosis (ABPA) and cross-reacts extensively with recombinant thioredoxin proteins from A.fumigatus (Asp f 28 and Asp f 29) and Mala s 13. Causes a positive skin reaction and induces proliferation of the human peripheral blood mononuclear cells in ABPA patients allergic to this protein. Acts as an IgE-binding self-antigen in ABPA patients allergic to fungal thioredoxin (PubMed:19032234). In atopic dermatitis (AD)-suffering patients allergic to M.sympodialis, a cross-reactivity between Mala s 13 and this protein can be detected in T-cells of the peripheral blood and skin. Keratinocytes stimulated by interferon (IFN)-alpha and tumor necrosis factor (TNF)-alpha release thioredoxin, which then becomes available for cross-reactivity with Mala s 13-specific T cells. The autoreactive T cells identified include T-helper 1 (Th1), T-helper 2 (Th2), T-helper 17 (Th17) and T-helper 22 (Th22) phenotypes. Skinhoming T cells autoreactive to this protein may be relevant for cutaneous inflammation in patients with AD (PubMed:21489611).SIMILARITY Belongs to the thioredoxin family.UniProtP105992EQUAL105EQUALReactome DB_ID: 12502771Thioredoxin:TXNIP [cytosol]Thioredoxin:TXNIPReactome DB_ID: 125024611EQUAL391EQUALReactome DB_ID: 6600012EQUAL105EQUALReactome Database ID Release 751250277Database 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=1250277ReactomeR-HSA-12502771Reactome 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-HSA-1250277.1Reactome Database ID Release 751250264Database 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=1250264ReactomeR-HSA-12502642Reactome 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-HSA-1250264.210419473Pubmed1999Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expressionNishiyama, AMatsui, MIwata, SHirota, KMasutani, HNakamura, HTakagi, YSono, HGon, YYodoi, JJ Biol Chem 274:21645-5017603038Pubmed2007Regulation of the bioavailability of thioredoxin in the lens by a specific thioredoxin-binding protein (TBP-2)Liyanage, NPFernando, MRLou, MFExp Eye Res 85:270-9ROS oxidize thioredoxinROS oxidize thioredoxinThe 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.Authored: Jupe, S, 2011-04-28Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 12502431reactive oxygen species [ChEBI:26523]reactive oxygen speciesChEBI26523Reactome DB_ID: 6600012EQUAL105EQUALReactome DB_ID: 736681Intra-chain Crosslink via L-cystine (cross-link) at 32 and 3532EQUALL-cystine (cross-link)2EQUAL105EQUALReactome Database ID Release 751250280Database 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=1250280ReactomeR-HSA-12502801Reactome 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-HSA-1250280.117132626Pubmed2007ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophagesCruz, CMRinna, AForman, HJVentura, ALPersechini, PMOjcius, DMJ Biol Chem 282:2871-920023662Pubmed2010Thioredoxin-interacting protein links oxidative stress to inflammasome activationZhou, RTardivel, AThorens, BChoi, ITschopp, JürgNat Immunol 11:136-4018403674Pubmed2008Innate immune activation through Nalp3 inflammasome sensing of asbestos and silicaDostert, CPétrilli, VVan Bruggen, RSteele, CMossman, BTTschopp, JürgScience 320:674-7TXNIP is released from oxidized thioredoxinTXNIP is released from oxidized thioredoxinROS induce the dissociation of TXNIP from thioredoxin, freeing TXNIP to subsequently bind NLRP3 and bring about activation of the NLRP3 inflammasome (Zhou et al. 2010). Authored: Jupe, S, 2011-04-28Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 12502491Oxidized thioredoxin:TXNIP [cytosol]Oxidized thioredoxin:TXNIPReactome DB_ID: 125024611EQUAL391EQUALReactome DB_ID: 736681Intra-chain Crosslink via L-cystine (cross-link) at 32 and 3532EQUAL2EQUAL105EQUALReactome Database ID Release 751250249Database 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=1250249ReactomeR-HSA-12502491Reactome 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-HSA-1250249.1Reactome DB_ID: 125024611EQUAL391EQUALReactome DB_ID: 736681Intra-chain Crosslink via L-cystine (cross-link) at 32 and 3532EQUAL2EQUAL105EQUALReactome Database ID Release 751250253Database 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=1250253ReactomeR-HSA-12502532Reactome 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-HSA-1250253.2Expression of NLRP3 geneExpression of NLRP3 geneTwo signals are required for NLRP3 inflammasome activation. Signal 1, also known as the priming signal, is mediated by microbial ligands recognised by TLRs or cytokines such as TNF-α which activate the NF-κB pathway, leading to upregulation of pro-IL-1β and NLRP3 protein levels (Bauernfeind et al. 2009, Jo et al. 2016).Authored: Jassal, Bijay, 2018-03-28Reviewed: Jo, Eun-Kyeong, 2018-03-29Edited: Jassal, Bijay, 2018-03-28Reactome DB_ID: 96039021nucleoplasmGO0005654ENSEMBL:ENSG00000162711 NLRP3NALP3NLRP3C1orf7PYPAF1CIAS1ENSEMBLENSG00000162711Reactome DB_ID: 56118911EQUAL1036EQUALReactome Database ID Release 759603905Database 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=9603905ReactomeR-HSA-96039052Reactome 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-HSA-9603905.219570822Pubmed2009Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expressionBauernfeind, FGHorvath, GStutz, AAlnemri, ESMacDonald, KSpeert, DFernandes-Alnemri, TWu, JMonks, BGFitzgerald, Katherine AHornung, VLatz, EJ Immunol 183:787-9126549800Pubmed2016Molecular mechanisms regulating NLRP3 inflammasome activationJo, Eun-KyeongKim, Jin KyungShin, Dong-MinSasakawa, ChihiroCell. Mol. Immunol. 13:148-59ACTIVATIONIn the absence of TLR agonist 'priming', inflammasome dependent caspase-1 activation is observed but IL-1 beta secretion is minimal. This is primarily because pro-IL1 beta is not expressed in most cells until stimulated by proinflammatory signals such as TNF or LPS that activate NFkappaB. NFkappaB induces expression of pro-IL1beta that can be activated by caspase-1.Reactome Database ID Release 759603907Database 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=9603907Reactome DB_ID: 177673NFkB Complex [nucleoplasm]NFkB ComplexConverted from EntitySet in ReactomeReactome DB_ID: 1776621Nuclear factor NF-kappa-B [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNFKB2(1-454) [nucleoplasm]NFKB1(1-433) [nucleoplasm]UniProtQ00653UniProtP19838Reactome DB_ID: 1776761UniProt:Q04206 RELARELANFKB3RELAFUNCTION NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The heterodimeric RELA-NFKB1 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. The NF-kappa-B heterodimeric RELA-NFKB1 and RELA-REL complexes, for instance, function as transcriptional activators. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. The inhibitory effect of I-kappa-B on NF-kappa-B through retention in the cytoplasm is exerted primarily through the interaction with RELA. RELA shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Beside its activity as a direct transcriptional activator, it is also able to modulate promoters accessibility to transcription factors and thereby indirectly regulate gene expression. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1. Essential for cytokine gene expression in T-cells (PubMed:15790681). The NF-kappa-B homodimeric RELA-RELA complex appears to be involved in invasin-mediated activation of IL-8 expression.SUBUNIT Component of the NF-kappa-B p65-p50 complex. Component of the NF-kappa-B p65-c-Rel complex. Homodimer; component of the NF-kappa-B p65-p65 complex. Component of the NF-kappa-B p65-p52 complex. May interact with ETHE1. Binds TLE5 and TLE1. Interacts with TP53BP2. Binds to and is phosphorylated by the activated form of either RPS6KA4 or RPS6KA5. Interacts with ING4 and this interaction may be indirect. Interacts with CARM1, USP48 and UNC5CL. Interacts with IRAK1BP1 (By similarity). Interacts with NFKBID (By similarity). Interacts with NFKBIA (PubMed:1493333). Interacts with GSK3B. Interacts with NFKBIB (By similarity). Interacts with NFKBIE. Interacts with NFKBIZ. Interacts with EHMT1 (via ANK repeats) (By similarity). Part of a 70-90 kDa complex at least consisting of CHUK, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14. Interacts with HDAC3; HDAC3 mediates the deacetylation of RELA. Interacts with HDAC1; the interaction requires non-phosphorylated RELA. Interacts with CBP; the interaction requires phosphorylated RELA. Interacts (phosphorylated at 'Thr-254') with PIN1; the interaction inhibits p65 binding to NFKBIA. Interacts with SOCS1. Interacts with UXT. Interacts with MTDH and PHF11. Interacts with ARRB2. Interacts with NFKBIA (when phosphorylated), the interaction is direct; phosphorylated NFKBIA is part of a SCF(BTRC)-like complex lacking CUL1. Interacts with RNF25. Interacts (via C-terminus) with DDX1. Interacts with UFL1 and COMMD1. Interacts with BRMS1; this promotes deacetylation of 'Lys-310'. Interacts with NOTCH2 (By similarity). Directly interacts with MEN1; this interaction represses NFKB-mediated transactivation. Interacts with AKIP1, which promotes the phosphorylation and nuclear retention of RELA. Interacts (via the RHD) with GFI1; the interaction, after bacterial lipopolysaccharide (LPS) stimulation, inhibits the transcriptional activity by interfering with the DNA-binding activity to target gene promoter DNA. Interacts (when acetylated at Lys-310) with BRD4; leading to activation of the NF-kappa-B pathway. Interacts with MEFV. Interacts with CLOCK (By similarity). Interacts (via N-terminus) with CPEN1; this interaction induces proteolytic cleavage of p65/RELA subunit and inhibition of NF-kappa-B transcriptional activity (PubMed:18212740). Interacts with FOXP3. Interacts with CDK5RAP3; stimulates the interaction of RELA with HDAC1, HDAC2 and HDAC3 thereby inhibiting NF-kappa-B transcriptional activity (PubMed:17785205). Interacts with DHX9; this interaction is direct and activates NF-kappa-B-mediated transcription (PubMed:15355351). Interacts with LRRC25 (PubMed:29044191). Interacts with TBX21 (By similarity). Interacts with KAT2A (By similarity). Interacts with ZBTB7A; involved in the control by RELA of the accessibility of target gene promoters (PubMed:29813070). Directly interacts with DDX3X; this interaction may trap RELA in the cytoplasm, impairing nuclear relocalization upon TNF activating signals (PubMed:27736973).SUBUNIT (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein M2-1.SUBUNIT (Microbial infection) Interacts with molluscum contagiosum virus MC132.SUBUNIT (Microbial infection) Interacts with herpes virus 8 virus protein LANA1.DOMAIN The transcriptional activation domain 3/TA3 does not participate in the direct transcriptional activity of RELA but is involved in the control by RELA of the accessibility of target gene promoters. Mediates interaction with ZBTB7A.DOMAIN The transcriptional activation domain 1/TA1 and the transcriptional activation domain 2/TA2 have direct transcriptional activation properties (By similarity). The 9aaTAD motif found within the transcriptional activation domain 2 is a conserved motif present in a large number of transcription factors that is required for their transcriptional transactivation activity (PubMed:17467953).PTM Ubiquitinated by RNF182, leading to its proteasomal degradation. Degradation is required for termination of NF-kappa-B response.PTM Monomethylated at Lys-310 by SETD6. Monomethylation at Lys-310 is recognized by the ANK repeats of EHMT1 and promotes the formation of repressed chromatin at target genes, leading to down-regulation of NF-kappa-B transcription factor activity. Phosphorylation at Ser-311 disrupts the interaction with EHMT1 without preventing monomethylation at Lys-310 and relieves the repression of target genes (By similarity).PTM Phosphorylation at Ser-311 disrupts the interaction with EHMT1 and promotes transcription factor activity (By similarity). Phosphorylation on Ser-536 stimulates acetylation on Lys-310 and interaction with CBP; the phosphorylated and acetylated forms show enhanced transcriptional activity. Phosphorylation at Ser-276 by RPS6KA4 and RPS6KA5 promotes its transactivation and transcriptional activities.PTM Reversibly acetylated; the acetylation seems to be mediated by CBP, the deacetylation by HDAC3 and SIRT2. Acetylation at Lys-122 enhances DNA binding and impairs association with NFKBIA. Acetylation at Lys-310 is required for full transcriptional activity in the absence of effects on DNA binding and NFKBIA association. Acetylation at Lys-310 promotes interaction with BRD4. Acetylation can also lower DNA-binding and results in nuclear export. Interaction with BRMS1 promotes deacetylation of Lys-310. Lys-310 is deacetylated by SIRT2.PTM S-nitrosylation of Cys-38 inactivates the enzyme activity.PTM Sulfhydration at Cys-38 mediates the anti-apoptotic activity by promoting the interaction with RPS3 and activating the transcription factor activity.PTM Sumoylation by PIAS3 negatively regulates DNA-bound activated NF-kappa-B.PTM Proteolytically cleaved within a conserved N-terminus region required for base-specific contact with DNA in a CPEN1-mediated manner, and hence inhibits NF-kappa-B transcriptional activity (PubMed:18212740).DISEASE A chromosomal aberration involving C11orf95 is found in more than two-thirds of supratentorial ependymomas. Translocation with C11orf95 produces a C11orf95-RELA fusion protein. C11orf95-RELA translocations are potent oncogenes that probably transform neural stem cells by driving an aberrant NF-kappa-B transcription program (PubMed:24553141).UniProtQ042061EQUAL551EQUALReactome Database ID Release 75177673Database 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=177673ReactomeR-HSA-1776731Reactome 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-HSA-177673.1TXNIP binds NLRP3TXNIP binds NLRP3Thioredoxin-interacting protein (TXNIP) binds NLRP3. Reactive oxygen species (ROS) such as H2O2 increase this interaction, while the ROS inhibitor APDC blocks it (Zhou et al. 2010). This interaction is proposed to activate the NLRP3 inflammasome.Authored: Jupe, S, 2011-04-28Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 125024611EQUAL391EQUALReactome DB_ID: 56118911EQUAL1036EQUALReactome DB_ID: 12502851TXNIP:NLRP3 [cytosol]TXNIP:NLRP3Reactome DB_ID: 125024611EQUAL391EQUALReactome DB_ID: 56118911EQUAL1036EQUALReactome Database ID Release 751250285Database 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=1250285ReactomeR-HSA-12502851Reactome 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-HSA-1250285.1Reactome Database ID Release 751250272Database 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=1250272ReactomeR-HSA-12502723Reactome 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-HSA-1250272.3NLRP3 activation by small moleculesNLRP3 activation by small moleculesThe 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.Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 8740861Converted from EntitySet in ReactomeReactome DB_ID: 8772451NLRP3 elicitor small molecules [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityHUA [cytosol]Asb [cytosol]SiO2 [cytosol]ChEBI16336ChEBI46661ChEBI30563Reactome DB_ID: 8772261NLRP3 elicitor small molecules:NLRP3 [cytosol]NLRP3 elicitor small molecules:NLRP3Converted from EntitySet in ReactomeReactome DB_ID: 8772451Reactome DB_ID: 56118911EQUAL1036EQUALReactome Database ID Release 75877226Database 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=877226ReactomeR-HSA-8772261Reactome 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-HSA-877226.1Reactome DB_ID: 8741121Reactome Database ID Release 751306876Database 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=1306876ReactomeR-HSA-13068762Reactome 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-HSA-1306876.218280002Pubmed2008Intracellular pattern-recognition receptorsDostert, CMeylan, ETschopp, JürgAdv Drug Deliv Rev 60:830-4012766759Pubmed2003NODs: intracellular proteins involved in inflammation and apoptosisInohara, NNunez, GNat Rev Immunol 3:371-8211607846Pubmed2001The NOD: a signaling module that regulates apoptosis and host defense against pathogensInohara, NNunez, GOncogene 20:6473-8117121814Pubmed2007Pannexin-1 couples to maitotoxin- and nigericin-induced interleukin-1beta release through a dye uptake-independent pathwayPelegrin, PSurprenant, AJ Biol Chem 282:2386-9418604214Pubmed2008Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilizationHornung, VBauernfeind, FGHalle, ASamstad, EOKono, HRock, KLFitzgerald, Katherine ALatz, ENat Immunol 9:847-5619826485Pubmed2009Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cellsCraven, RRGao, XAllen, ICGris, DBubeck Wardenburg, JMcElvania-Tekippe, ETing, JPDuncan, JAPLoS One 4:e744619501527Pubmed2009The NLRP3 inflammasome: a sensor of immune danger signalsCassel, SLJoly, SSutterwala, FSSemin Immunol 21:194-820303873Pubmed2010The inflammasomesSchroder, KTschopp, JürgCell 140:821-3218604209Pubmed2008The NALP3 inflammasome is involved in the innate immune response to amyloid-betaHalle, AHornung, VPetzold, GCStewart, CRMonks, BGReinheckel, ThomasFitzgerald, Katherine ALatz, EMoore, KJGolenbock, DTNat Immunol 9:857-65NLRP3 activation by elicitor proteinsNLRP3 activation by elicitor proteinsThe 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.Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 8740861Converted from EntitySet in ReactomeReactome DB_ID: 90383831NLRP3 elicitor proteins [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityAlpha-hemolysin [cytosol]APP(672-711) [cytosol]UniProtP09616UniProtP05067Reactome DB_ID: 8741121Reactome DB_ID: 13068791NLRP3 elicitor proteins:NLRP3 [cytosol]NLRP3 elicitor proteins:NLRP3Reactome DB_ID: 8740861Converted from EntitySet in ReactomeReactome DB_ID: 90383831Reactome Database ID Release 751306879Database 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=1306879ReactomeR-HSA-13068794Reactome 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-HSA-1306879.4Reactome Database ID Release 75844440Database 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=844440ReactomeR-HSA-8444402Reactome 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-HSA-844440.2NLRP3 oligomerizes via NACHT domainsNLRP3 oligomerizes via NACHT domainsNLRP3 contains a NACHT/NOD domain that in related proteins is responsible for oligomerization (Inohara & Nunez 2001, 2003). NLRP1 forms oligomers upon stimulation with MDP (Faustin et al. 2007) and the enforced oligomerization of NLRP3 PYD domains enhances ASC-dependent effects on apoptosis (Dowds et al. 2002). NOD-mediated oligomerization is widely considered to be part of the activation process for the NLRP3 inflammasome (Schroder et al. 2010, Schroder & Tschopp, 2010). The extent of oligomerization is not known, but models based on the the apoptotic initiator protein Apaf-1 suggest a posible heptameric platform (Proell et al. 2008).Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2010-04-22Converted from EntitySet in ReactomeReactome DB_ID: 13068781NLRP3 elicitors:NLRP3 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome DB_ID: 12964091NLRP3 elicitors:NLRP3 oligomer [cytosol]NLRP3 elicitors:NLRP3 oligomerReactome Database ID Release 751296421Database 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=1296421ReactomeR-HSA-12964211Reactome 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-HSA-1296421.112615073Pubmed2003Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene productDowds, TAMasumoto, JChen, FFOgura, YInohara, NNunez, GBiochem Biophys Res Commun 302:575-8017703304Pubmed2007NALP inflammasomes: a central role in innate immunityMartinon, FGaide, OPétrilli, VMayor, ATschopp, JürgSemin Immunopathol 29:213-2917349957Pubmed2007Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activationFaustin, BLartigue, LBruey, JMLuciano, FSergienko, EBailly-Maitre, BVolkmann, NHanein, DRouiller, IReed, JCMol Cell 25:713-2420075245Pubmed2010The NLRP3 inflammasome: a sensor for metabolic danger?Schroder, KZhou, RTschopp, JürgScience 327:296-30018446235Pubmed2008The Nod-like receptor (NLR) family: a tale of similarities and differencesProell, MRiedl, SJFritz, JHRojas, AMSchwarzenbacher, RPLoS One 3:e2119ASC is recruited via a PYD-PYD interactionASC is recruited via a PYD-PYD interactionNLRP3 interacts with ASC (Manji et al. 2003) via their PYD domains (Dowds et al. 2004). NLRP3 oligomerization leads to PYD domain clustering which is believed to facilitate the interaction of NLRP3 with the PYD domain of ASC (Schroder & Tschopp, 2010).Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 12964091Reactome DB_ID: 5611911UniProt:Q9ULZ3 PYCARDPYCARDPYCARDTMS1ASCCARD5FUNCTION 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. Isoform 2 may have a regulating effect on the function as inflammasome adapter. Isoform 3 seems to inhibit inflammasome-mediated maturation of interleukin-1 beta. 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. Homooligomers can form disk-like particles of approximately 12 nm diameter and approximately 1 nm height. Next to isoform 1, also isoform 2 and isoform 3 may be involved in oligomerization leading to functional regulation. Component of several inflammasomes containing one pattern recognition receptor/sensor, such as NLRP1, NLRP2, NLRP3, AIM2, MEFV or NOD2, and probably NLRC4, NLRP12 or IFI16. Major component of the ASC pyroptosome, a 1-2 um supramolecular assembly (one per macrophage cell) which consists of oligomerized PYCARD dimers and CASP1. 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. Interacts with NLRP3; the interaction requires the homooligomerization of NLRP3. Interacts with NLRP2, NLRC4, MEFV, CARD16, AIM2, IFI16, NOD2, DDX58, RIPK2, PYDC1, PYDC2, NLRP10, CASP8, CHUK, IKBKB and BAX.TISSUE SPECIFICITY Widely expressed at low levels. Detected in peripheral blood leukocytes, lung, small intestine, spleen, thymus, colon and at lower levels in placenta, liver and kidney. Very low expression in skeletal muscle, heart and brain. Expressed in lung epithelial cells (at protein level) (PubMed:23229815). Detected in the leukemia cell lines HL-60 and U-937, but not in Jurkat T-cell lymphoma and Daudi Burkitt's lymphoma. Detected in the melanoma cell line WM35, but not in WM793. Not detected in HeLa cervical carcinoma cells and MOLT-4 lymphocytic leukemia cells.INDUCTION In macrophages, up-regulated by endocannabinoid anandamide/AEA.DOMAIN The CARD domain mediates interaction with CASP1 and NLRC4 (PubMed:14634131 and PubMed:11967258).DOMAIN The pyrin domain mediates homotypic interactions with pyrin domains of proteins such as of NLRP3, PYDC1, PYDC2 and AIM2.PTM Phosphorylated.MISCELLANEOUS In breast tumorigenesis, methylation-mediated silencing may affect genes and proteins that act as positive mediators of cell death.UniProtQ9ULZ31EQUAL195EQUALReactome DB_ID: 8773811NLRP3 elicitors:NLRP3 oligomer:ASC [cytosol]NLRP3 elicitors:NLRP3 oligomer:ASCReactome DB_ID: 12964091Reactome DB_ID: 56119111EQUAL195EQUALReactome Database ID Release 75877381Database 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=877381ReactomeR-HSA-8773812Reactome 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-HSA-877381.2Reactome Database ID Release 75844610Database 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=844610ReactomeR-HSA-8446102Reactome 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-HSA-844610.211786556Pubmed2002PYPAF1, a PYRIN-containing Apaf1-like protein that assembles with ASC and regulates activation of NF-kappa BManji, GAWang, LGeddes, BJBrown, MMerriam, SAl-Garawi, AMak, SLora, JMBriskin, MJurman, MCao, JDiStefano, PSBertin, JJ Biol Chem 277:11570-5The CARD domain of ASC recruits Procaspase-1The CARD domain of ASC recruits Procaspase-1Procaspase-1 is recruited via a CARD-CARD interaction with ASC. This creates procaspase-1 clustering which is believed to stimulate procaspase-1 autocleavage, generating the p10/p20 fragments that assemble into the active capsase-1 tetramer (Schroder & Tschopp, 2010).Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 8773811Reactome DB_ID: 4486921UniProt:P29466 CASP1CASP1IL1BCCASP1IL1BCEFUNCTION Thiol protease that cleaves IL-1 beta between an Asp and an Ala, releasing the mature cytokine which is involved in a variety of inflammatory processes. Important for defense against pathogens. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Can also promote apoptosis. Upon inflammasome activation, during DNA virus infection but not RNA virus challenge, controls antiviral immunity through the cleavage of CGAS, rendering it inactive (PubMed:28314590). In apoptotic cells, cleaves SPHK2 which is released from cells and remains enzymatically active extracellularly (PubMed:20197547).ACTIVITY REGULATION Specifically inhibited by the cowpox virus Crma protein.SUBUNIT Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (p20) and a 10 kDa (p10) subunit. The p20 subunit can also form a heterodimer with the epsilon isoform which then has an inhibitory effect. May be a component of the inflammasome, a protein complex which also includes PYCARD, CARD8 and NALP2 and whose function would be the activation of proinflammatory caspases. Both the p10 and p20 subunits interact with MEFV. Interacts with CARD17/INCA and CARD18. Interacts with SERPINB1; this interaction regulates CASP1 activity.TISSUE SPECIFICITY Expressed in larger amounts in spleen and lung. Detected in liver, heart, small intestine, colon, thymus, prostate, skeletal muscle, peripheral blood leukocytes, kidney and testis. No expression in the brain.INDUCTION Transcription and translation induced by M.tuberculosis and a number of different M.tuberculosis components; EsxA is the most potent activator tested (at protein level) (PubMed:20148899).PTM The two subunits are derived from the precursor sequence by an autocatalytic mechanism.SIMILARITY Belongs to the peptidase C14A family.UniProtP294661EQUAL404EQUALReactome DB_ID: 9254581NLRP3 elicitors:NLRP3 oligomer:ASC:Procaspase-1 [cytosol]NLRP3 elicitors:NLRP3 oligomer:ASC:Procaspase-1Reactome DB_ID: 8773811Reactome DB_ID: 44869211EQUAL404EQUALReactome Database ID Release 75925458Database 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=925458ReactomeR-HSA-9254582Reactome 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-HSA-925458.2Reactome Database ID Release 75844612Database 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=844612ReactomeR-HSA-8446122Reactome 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-HSA-844612.211967258Pubmed2002The PYRIN-CARD protein ASC is an activating adaptor for caspase-1Srinivasula, SMPoyet, JLRazmara, MDatta, PZhang, ZAlnemri, ESJ Biol Chem 277:21119-2212191486Pubmed2002The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-betaMartinon, FBurns, KTschopp, JürgMol Cell 10:417-26PSTPIP1 binds PyrinPSTPIP1 binds PyrinProline-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).Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Edited: Jupe, S, 2011-04-28Reactome DB_ID: 8792021Pyrin trimer [cytosol]Pyrin trimerReactome DB_ID: 8773553UniProt:O15553 MEFVMEFVMEFVTRIM20MEFFUNCTION Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma. Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1, ATG16L1, and ATG8 family members and recognizes specific autophagy targets, thus coordinating target recognition with assembly of the autophagic apparatus and initiation of autophagy. Acts as an autophagy receptor for the degradation of several inflammasome components, including CASP1, NLRP1 and NLRP3, hence preventing excessive IL1B- and IL18-mediated inflammation (PubMed:16785446, PubMed:17431422, PubMed:26347139). However, it may also have a positive effect in the inflammatory pathway. In different experimental systems, it has been shown to activate IL1B production (PubMed:16037825). It has also been shown to be required for PSTPIP1-induced PYCARD oligomerization and for formation of inflammasomes. Recruits PSTPIP1 to inflammasomes, and is required for PSTPIP1 oligomerization (PubMed:10807793, PubMed:11468188, PubMed:17964261, PubMed:18577712, PubMed:19109554, PubMed:19584923).SUBUNIT Homotrimer. Interacts (via the B box-type zinc finger) with PSTPIP1 (PubMed:14595024, PubMed:17964261, PubMed:19109554). Interacts (via the B30.2/SPRY domain) with several components of the inflammasome complex, including CASP1 p20 and p10 subunits, CASP5, PYCARD, NLRP1, NLRP2 AND NLRP3, as well as with unprocessed IL1B; this interaction may lead to autophagic degradation of these proteins (PubMed:11498534, PubMed:16785446, PubMed:17431422, PubMed:17964261, PubMed:26347139). Interacts with NFKBIA and RELA (PubMed:18577712). Interacts weakly with VASP and ACTR3 (PubMed:19109554). Interacts with active ULK1 (phosphorylated on 'Ser-317') and BECN1 simultaneously. Also interacts with ATG16L1 (via WD repeats), and with ATG8 family members, including GABARAP, GABARAPL1 and, to a lesser extent, GABARAPL2, MAP1LC3A/LC3A and MAP1LC3C/LC3C. Interacts with TRIM21 (PubMed:26347139).TISSUE SPECIFICITY Expressed in peripheral blood leukocytes, particularly in mature granulocytes and to a lesser extent in monocytes but not in lymphocytes. Detected in spleen, lung and muscle, probably as a result of leukocyte infiltration in these tissues. Not expressed in thymus, prostate, testis, ovary, small intestine, colon, heart, brain, placenta, liver, kidney, pancreas. Expression detected in several myeloid leukemic, colon cancer, and prostate cancer cell lines.DEVELOPMENTAL STAGE First detected in bone marrow promyelocytes. Expression increases throughout myelocyte differentiation and peaks in the mature myelomonocytic cells.INDUCTION In monocytes, up-regulated by treatment with colchicine and IFN-alpha, by the proinflammatory cytokines IFNG/IFN-gamma and TNF, by bacterial lipopolysaccharides (LPS) and by retroviral infection. Repressed in monocytes by the antiinflammatory cytokines IL10/interleukin-10, TGFB1 and IL4/interleukin-4. In neutrophils and macrophages, up-regulated by IFNG/IFN-gamma with a peak after 8 hours of treatment.DOMAIN The B box-type zinc finger interacts, possibly intramolecularly, with the pyrin domain; this may be an autoinhibitory mechanism released by PSTPIP1 binding.PTM Cleaved by CASP1 (Probable). The N-terminal cleavage product localizes to the nucleus as a filamentous network and to the cytoplasm, interacts more strongly with RELA and NFKBIA than the full-length protein, enhances the nuclear localization of RELA and induces NFKBIA proteolysis. The C-terminal cleavage product localizes to the cytoplasm.MISCELLANEOUS Degraded along with the delivery of its substrates to autolysosomal compartments (at protein level).UniProtO155531EQUAL781EQUALReactome Database ID Release 75879202Database 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=879202ReactomeR-HSA-8792021Reactome 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-HSA-879202.1Reactome DB_ID: 8792131PSTPIP1 trimer [cytosol]PSTPIP1 trimerReactome DB_ID: 8792203UniProt:O43586 PSTPIP1PSTPIP1PSTPIP1CD2BP1FUNCTION Involved in regulation of the actin cytoskeleton. May regulate WAS actin-bundling activity. Bridges the interaction between ABL1 and PTPN18 leading to ABL1 dephosphorylation. May play a role as a scaffold protein between PTPN12 and WAS and allow PTPN12 to dephosphorylate WAS. Has the potential to physically couple CD2 and CD2AP to WAS. Acts downstream of CD2 and CD2AP to recruit WAS to the T-cell:APC contact site so as to promote the actin polymerization required for synapse induction during T-cell activation (By similarity). Down-regulates CD2-stimulated adhesion through the coupling of PTPN12 to CD2. Also has a role in innate immunity and the inflammatory response. Recruited to inflammasomes by MEFV. Induces formation of pyroptosomes, large supramolecular structures composed of oligomerized PYCARD dimers which form prior to inflammatory apoptosis. Binding to MEFV allows MEFV to bind to PYCARD and facilitates pyroptosome formation. Regulates endocytosis and cell migration in neutrophils.SUBUNIT Homodimer (PubMed:19584923). Homotrimer (PubMed:17964261). Interacts (via coiled-coil domain) with CD2AP, PTPN12 and PTPN18. Interacts (via SH3 domain) with ABL1 and WAS. Interacts (via SH3 and coiled-coil domains) with MEFV (via B-box zinc finger); the interaction allows binding of MEFV to PYCARD and facilitates formation of PYCARD pyroptosomes. Interacts with CD2, DNM2 and FASLG.TISSUE SPECIFICITY Highly expressed in the peripheral blood leukocytes, granulocytes and monocytes, namely in T-cells and natural killer cells, and in spleen. Weakly expressed in the thymus, small intestine, lung and placenta.DOMAIN The F-BAR domain is important for filament formation. The SH3 domain is not required for filament formation or localization to the uropod.PTM Dephosphorylated on Tyr-345 by PTPN18, this event negatively regulates the association of PSTPIP1 with SH2 domain-containing proteins as tyrosine kinase. Phosphorylation of Tyr-345 is probably required for subsequent phosphorylation at other tyrosine residues. Phosphorylation is induced by activation of the EGFR and PDGFR in a ABL1 dependent manner. The phosphorylation regulates the interaction with WAS and with MEFV (By similarity).UniProtO435861EQUAL416EQUALReactome Database ID Release 75879213Database 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=879213ReactomeR-HSA-8792131Reactome 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-HSA-879213.1Reactome DB_ID: 8791971PSTPIP1 trimer:Pyrin trimer [cytosol]PSTPIP1 trimer:Pyrin trimerReactome DB_ID: 8792021Reactome DB_ID: 8792131Reactome Database ID Release 75879197Database 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=879197ReactomeR-HSA-8791971Reactome 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-HSA-879197.1Reactome Database ID Release 75879221Database 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=879221ReactomeR-HSA-8792212Reactome 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-HSA-879221.221083527Pubmed2010Inflammasomes and their activationKhare, SLuc, NDorfleutner, AStehlik, CCrit Rev Immunol 30:463-8717964261Pubmed2007Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutantsYu, JWFernandes-Alnemri, TDatta, PWu, JJuliana, CSolorzano, LMcCormick, MZhang, ZAlnemri, ESMol Cell 28:214-279857189Pubmed1998A cdc15-like adaptor protein (CD2BP1) interacts with the CD2 cytoplasmic domain and regulates CD2-triggered adhesionLi, JNishizawa, KAn, WHussey, RELialios, FESalgia, RSunder-Plassmann, RReinherz, ELEMBO J 17:7320-3614595024Pubmed2003Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathwayShoham, NGCentola, MMansfield, EHull, KMWood, GWise, CAKastner, DLProc Natl Acad Sci U S A 100:13501-6Pyrin binds ASCPyrin binds ASCTrimeric 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).Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 8792021Reactome DB_ID: 56119131EQUAL195EQUALReactome DB_ID: 8773521Pyrin trimer:ASC [cytosol]Pyrin trimer:ASCReactome DB_ID: 8792021Reactome DB_ID: 56119131EQUAL195EQUALReactome Database ID Release 75877352Database 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=877352ReactomeR-HSA-8773521Reactome 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-HSA-877352.1Reactome Database ID Release 75877361Database 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=877361ReactomeR-HSA-8773612Reactome 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-HSA-877361.211498534Pubmed2001Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosisRichards, NSchaner, PDiaz, AStuckey, JShelden, EWadhwa, AGumucio, DLJ Biol Chem 276:39320-912667444Pubmed2003Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosisChae, JJKomarow, HDCheng, JWood, GRaben, NLiu, PPKastner, DLMol Cell 11:591-604Reactome Database ID Release 75844456Database 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=844456ReactomeR-HSA-8444564Reactome 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-HSA-844456.416498449Pubmed2006CATERPILLERs, pyrin and hereditary immunological disordersTing, JPKastner, DLHoffman, HMNat Rev Immunol 6:183-95The NLRP1 inflammasomeThe NLRP1 inflammasomeNLRP1 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). Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Bcl-2 and Bcl-XL bind NLRP1Bcl-2 and Bcl-XL bind NLRP1The 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.Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 5611961UniProt:Q9C000 NLRP1NLRP1NACNALP1CARD7NLRP1DEFCAPKIAA0926FUNCTION As the sensor component of the NLRP1 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 NLRP1, CASP1, and possibly PYCARD. Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu. Activation of NLRP1 inflammasome is also required for HMGB1 secretion. The active cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death (PubMed:22665479, PubMed:17418785). May be activated by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, in a NOD2-dependent manner (PubMed:18511561). Contrary to its mouse ortholog, not activated by Bacillus anthracis lethal toxin (PubMed:19651869). It is unclear whether isoform 2 is involved in inflammasome formation. It is not cleaved within the FIIND domain, does not assemble into specks, nor promote IL1B release (PubMed:22665479). However, in an vitro cell-free system, it has been shown to be activated by MDP (PubMed:17349957). Binds ATP (PubMed:11113115, PubMed:15212762).SUBUNIT Sensor component of NLRP1 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. Classical inflammasomes consist of a signal sensor component, an adapter (ASC/PYCARD), which recruits an effector proinflammatory caspase (CASP1 and CASP5). This interaction initiates speck formation (nucleation) which greatly enhances further addition of soluble PYCARD molecules to the speck in a prion-like polymerization process. 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. In NLRP1 inflammasome, the role of PYCARD is not clear. Following activation, NLRP1 can directly interact with CASP1 (possibly through CARD domain) to form a functional inflammasome, although the presence of PYCARD increases CASP1 activity (PubMed:17418785, PubMed:17349957). In a different experimental system, neither CASP1-binding, NLRP1 inflammasome speck formation, nor IL1B release were observed in the absence of PYCARD (PubMed:22665479, PubMed:12191486). Hence PYCARD may not be necessary for NLRP1 and CASP1 interaction, but is required for speck formation and full inflammasome activity (By similarity). Homomer (PubMed:17349957). Interacts (via LRR repeats) with BCL2 and BCL2L1 (via the loop between motifs BH4 and BH3); these interactions reduce NLRP1 inflammasome-induced CASP1 activation and IL1B release, possibly by impairing NLRP1 interaction with PYCARD (PubMed:17418785). Interacts with NOD2; this interaction is enhanced in the presence of muramyl dipeptide (MDP) and increases IL1B release (PubMed:18511561). Interacts with EIF2AK2/PKR; this interaction requires EIF2AK2 activity, is accompanied by EIF2AK2 autophosphorylation and promotes inflammasome assembly in response to danger-associated signals (By similarity). Interacts with MEFV; this interaction targets NLRP1 to degradation by autophagy, hence preventing excessive IL1B- and IL18-mediated inflammation (PubMed:17431422, PubMed:26347139).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein F1 (PubMed:16439990).TISSUE SPECIFICITY Widely expressed (PubMed:11113115, PubMed:17164409). Abundantly expressed in primary immune cells (isoform 1 and isoform 2), including in neutrophils, monocytes/macrophages, dendritic cells (mostly Langerhans cells), and B- and T-lymphocytes (at protein level) (PubMed:15285719, PubMed:17164409). Strongly expressed in epithelial cells lining the glandular epithelium, such as that of the gastrointestinal tract (stomach, small intestine, colon), the respiratory tract (trachea and bronchi), and the endometrial and endocervical glands, gallbladder, prostate, and breast (at protein level). In testis, expressed in spermatogonia and primary spermatocytes, but not in Sertoli cells (at protein level). In the brain, expressed in neurons, in particular in pyramidal ones and in oligodendrocytes, but not detected in microglia (at protein level) (PubMed:17164409). Expressed in adult and fetal ocular tissues, including in adult and 24-week old fetal choroid, sclera, cornea, and optic nerve, as well as in adult retina and fetal retina/retinal pigment epithelium (PubMed:23349227). Highly expressed in the skin throughout the epidermis and in dermal fibroblasts, in both glabrous skin and plantar skin. It is detected in keratinocytes, but not in melanocytes. Expressed in epidermal appendages such as hair follicles (PubMed:27662089).DEVELOPMENTAL STAGE Associated with differentiation in stratified epithelia of the skin, esophagus, intestine, and cervix, as well as in the prostate gland. Undetectable in undifferentiated basal cells, but expressed in differentiated luminal secretory cells (PubMed:11113115). Expressed in differentiated macrophages and granulocytes, but not their precursors (at protein level) (PubMed:11113115, PubMed:15285719). In testis, also associated with cell differentiation, with conflicting results. Expressed in spermatogonia and primary spermatocytes, but not in cells from later differentiation stages, including secondary spermatocytes, spermatids, and spermatozoa (at protein level) (PubMed:17164409). Not detected in spermatocytes, nor spermatids, and strongly expressed in spermatozoa (at protein level) (PubMed:11113115).INDUCTION Up-regulated by ATF4 during endoplasmic reticulum (ER) stress response (PubMed:26086088). Up-regulated in arterial endothelial cells exposed to plasma from patients with peripheral arterial disease, but not to plasma from healthy controls (PubMed:24439873).DOMAIN The CARD domain, rather than the pyrin domain, is involved in the interaction with PYCARD, CASP1 and CASP5.DOMAIN The leucine-rich repeat (LRR) domain may be involved in autoinhibition in the absence of activating signal, possibly through intramolecular interaction with the NACHT domain.DOMAIN The FIIND (domain with function to find) region is involved in homomerization, but not in CASP1-binding (By similarity). Autocatalytic cleavage in this region occurs constitutively, prior to activation signals, and is required for inflammasome activity (IL1B release), possibly by facilitating CASP1 binding. Both N- and C-terminal fragments remain associated (PubMed:22665479, PubMed:22087307).MISCELLANEOUS In macrophages and dendritic cells, NLRP1 inflammasome activation of CASP1 and IL1B maturation can be dampened by direct contact with activated effector and memory T-cells. This effect may be mediated by hexameric TNF ligands, such as CD40LG.SIMILARITY Belongs to the NLRP family.UniProtQ9C0001EQUAL1473EQUALConverted from EntitySet in ReactomeReactome DB_ID: 8792091mitochondrial outer membraneGO0005741Bcl-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 PhysicalEntityBCL2 [mitochondrial outer membrane]BCL2L1 [mitochondrial outer membrane]UniProtP10415UniProtQ07817Reactome DB_ID: 8792181Bcl-2/Bcl-X(L):NLRP1 [mitochondrial outer membrane]Bcl-2/Bcl-X(L):NLRP1Reactome DB_ID: 56119611EQUAL1473EQUALConverted from EntitySet in ReactomeReactome DB_ID: 8792091Reactome Database ID Release 75879218Database 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=879218ReactomeR-HSA-8792181Reactome 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-HSA-879218.1Reactome Database ID Release 75879201Database 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=879201ReactomeR-HSA-8792011Reactome 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-HSA-879201.117418785Pubmed2007Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1Bruey, JMBruey-Sedano, NLuciano, FZhai, DBalpai, RXu, CKress, CLBailly-Maitre, BLi, XOsterman, AMatsuzawa, STerskikh, AVFaustin, BReed, JCCell 129:45-56NLRP1 senses MDPNLRP1 senses MDPIn 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.Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 56119611EQUAL1473EQUALReactome DB_ID: 7083411muramyl dipeptide [ChEBI:59414]muramyl dipeptideChEBI59414Reactome DB_ID: 8773701MDP:NLRP1 [cytosol]MDP:NLRP1Reactome DB_ID: 56119611EQUAL1473EQUALReactome DB_ID: 7083411Reactome Database ID Release 75877370Database 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=877370ReactomeR-HSA-8773701Reactome 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-HSA-877370.1Reactome Database ID Release 75844447Database 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=844447ReactomeR-HSA-8444471Reactome 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-HSA-844447.1MDP:NLRP1 binds ATPMDP:NLRP1 binds ATPMDP may induce a conformational change in NLRP1 which enables ATP binding, required for NLRP1 oligomerization (Faustin et al. 2007).Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 8773701Reactome DB_ID: 1135921Reactome DB_ID: 8792071MDP:NLRP1:ATP [cytosol]MDP:NLRP1:ATPReactome DB_ID: 8773701Reactome DB_ID: 1135921Reactome Database ID Release 75879207Database 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=879207ReactomeR-HSA-8792071Reactome 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-HSA-879207.1Reactome Database ID Release 75879222Database 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=879222ReactomeR-HSA-8792221Reactome 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-HSA-879222.1NLRP1 oligomerizesNLRP1 oligomerizesNLRP1 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.Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 8792071Reactome DB_ID: 12964121MDP:NLRP1:ATP oligomer [cytosol]MDP:NLRP1:ATP oligomerReactome Database ID Release 75844438Database 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=844438ReactomeR-HSA-8444381Reactome 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-HSA-844438.1Reactome Database ID Release 75844455Database 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=844455ReactomeR-HSA-8444551Reactome 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-HSA-844455.117850338Pubmed2008Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasomeWickliffe, KELeppla, Stephen HMoayeri, MahtabCell Microbiol 10:332-4316429160Pubmed2006Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxinBoyden, EDDietrich, WFNat Genet 38:240-4The IPAF inflammasomeThe IPAF inflammasomeThe IPAF (NLRC4) inflammasome can be activated by several stimuli, most notably by Gram-negative bacteria with either type III or type IV secretion systems that result in cytosolic flagellin, which is recognized by the IPAF inflammasome (Miao et al. 2006). IPAF also recognizes the rod-component of the type III secretion system which shares a sequence motif with flagellin that is essential for detection (Miao et al. 2010). Detection of Legionella and/or flagellin may also involve NAIP5 (Zamboni et al. 2006, Lightfield et al. 2008). IPAF contains a CARD domain and can interact directly with procaspase-1 (Poyet et al. 2001) but ASC increases the maximal activation of caspase-1 in response to S. typhimurium (Mariathasan et al. 2004), S. flexneri, and P. aeruginosa suggesting a possible collaboration with a PYD-containing NLRP for responses to these pathogens (Schroder & Tschopp, 2010). IPAF mediated caspase-1 activation can lead to a particular type of cell death called 'pyroptosis' (see Schroder & Tschopp 2010). Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28IPAF is activatedIPAF is activatedAlthough a direct interaction between IPAF and an activating ligand has not been demonstrated, IPAF can be activated by cytosolic flagellin either applied experimentally or resulting from the activity of the virulence-associated type III or V secretion systems (Franchi et al. 2006, Miao et al 2007, 2008). Activation can also be flagellin-independent (Suzuki et al. 2007, Sutterwala et al. 2007), suggesting alternative mechanisms that are likely to involve recognition of components of the bacterial type III secretion system (Miao et al. 2010). The LRR domain of IPAF appears to repress activity in the absence of a ligand as removal of this domain leads to constitutive activation (Poyet et al. 2001).Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 5611981UniProt:Q9NPP4 NLRC4NLRC4CLAN1UNQ6189/PRO20215CLANNLRC4IPAFCARD12FUNCTION Key component of inflammasomes that indirectly senses specific proteins from pathogenic bacteria and fungi and responds by assembling an inflammasome complex that promotes caspase-1 activation, cytokine production and macrophage pyroptosis (PubMed:15107016). The NLRC4 inflammasome is activated as part of the innate immune response to a range of intracellular bacteria (By similarity).SUBUNIT Homooligomer (PubMed:25385754). Homooligomerizes following activation of Naip proteins by pathogenic proteins such as S.typhimurium (Salmonella) flagellin or PrgJ. Component of the NLRC4 inflammasome, at least composed of NLRC4, caspase-1 (CASP1) and some NAIP family member (By similarity). Interacts with ASC, pro-caspase-1, NOD2, BCL10 and NALP1 (NAC) by CARD-CARD interaction. Interacts with EIF2AK2/PKR (PubMed:22801494).TISSUE SPECIFICITY Isoform 2 is expressed ubiquitously, although highly expressed in lung and spleen. Isoform 1 is highly expressed in lung, followed by leukocytes especially monocytes, lymph node, colon, brain, prostate, placenta, spleen, bone marrow and fetal liver. Isoform 4 is only detected in brain.DOMAIN In an autoinhibited form the C-terminal leucine-rich repeat (LRR) domain is positioned to sterically occlude one side of the NBD domain and consequently sequester NLRC4 in a monomeric state. An ADP-mediated interaction between the NBD and the WHD also contributes to the autoinhibition.PTM Phosphorylated at Ser-533 following infection of macrophages with S.typhimurium (Salmonella). Phosphorylation is essential for NLRC4 inflammasome function to promote caspase-1 activation and pyroptosis. PRKCD phosphorylates Ser-533 in vitro.UniProtQ9NPP41EQUAL1024EQUALConverted from EntitySet in ReactomeReactome DB_ID: 12523861IPAF elicitors [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityprgJ [cytosol]Salmonella typhimuriumNCBI Taxonomy90371UniProtP41785Reactome DB_ID: 8773941IPAF elicitors:NLRC4 [cytosol]IPAF elicitors:NLRC4Reactome DB_ID: 56119811EQUAL1024EQUALConverted from EntitySet in ReactomeReactome DB_ID: 12523861Reactome Database ID Release 75877394Database 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=877394ReactomeR-HSA-8773943Reactome 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-HSA-877394.3Reactome Database ID Release 75874084Database 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=874084ReactomeR-HSA-8740845Reactome 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-HSA-874084.516648852Pubmed2006Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophagesFranchi, LAmer, ABody-Malapel, MKanneganti, TDOzören, NJagirdar, RInohara, NVandenabeele, PBertin, JCoyle, AGrant, EPNunez, GNat Immunol 7:576-8218070936Pubmed2007Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasomeSutterwala, FSMijares, LALi, LOgura, YKazmierczak, BIFlavell, RAJ Exp Med 204:3235-4517696608Pubmed2007Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophagesSuzuki, TFranchi, LToma, CAshida, HOgawa, MYoshikawa, YMimuro, HInohara, NSasakawa, CNunez, GPLoS Pathog 3:e11120133635Pubmed2010Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasomeMiao, EAMao, DPYudkovsky, NBonneau, RLorang, CGWarren, SELeaf, IAAderem, AProc Natl Acad Sci U S A 107:3076-8018256184Pubmed2008Pseudomonas aeruginosa activates caspase 1 through IpafMiao, EAErnst, RKDors, MMao, DPAderem, AProc Natl Acad Sci U S A 105:2562-711390368Pubmed2001Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1Poyet, JLSrinivasula, SMTnani, MRazmara, MFernandes-Alnemri, TAlnemri, ESJ Biol Chem 276:28309-13IPAF binds procaspase-1IPAF binds procaspase-1IPAF contains an N-terminal CARD domain, a central nucleotide-binding domain, and a C-terminal regulatory leucine-rich repeat domain. IPAF associates with the CARD domain of procaspase-1 through a CARD-CARD interaction.Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 44869211EQUAL404EQUALReactome DB_ID: 8773941Reactome DB_ID: 8740831IPAF elicitors:NLRC4:Procaspase-1 [cytosol]IPAF elicitors:NLRC4:Procaspase-1Reactome DB_ID: 44869211EQUAL404EQUALReactome DB_ID: 8773941Reactome Database ID Release 75874083Database 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=874083ReactomeR-HSA-8740832Reactome 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-HSA-874083.2Reactome Database ID Release 75844617Database 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=844617ReactomeR-HSA-8446171Reactome 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-HSA-844617.1Reactome Database ID Release 75844623Database 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=844623ReactomeR-HSA-8446231Reactome 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-HSA-844623.115190255Pubmed2004Differential activation of the inflammasome by caspase-1 adaptors ASC and IpafMariathasan, SNewton, KMonack, DMVucic, DFrench, DMLee, WPRoose-Girma, MErickson, SDixit, VMNature 430:213-816648853Pubmed2006Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via IpafMiao, EAAlpuche-Aranda, CMDors, MClark, AEBader, MWMiller, SIAderem, ANat Immunol 7:569-7516444259Pubmed2006The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infectionZamboni, DSKobayashi, KSKohlsdorf, TOgura, YLong, EMVance, REKuida, KMariathasan, SDixit, VMFlavell, RADietrich, WFRoy, CRNat Immunol 7:318-2518724372Pubmed2008Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellinLightfield, KLPersson, JBrubaker, SWWitte, CEvon Moltke, JDunipace, EAHenry, TSun, YHCado, DDietrich, WFMonack, DMTsolis, RMVance, RENat Immunol 9:1171-8The AIM2 inflammasomeThe AIM2 inflammasomeAIM2 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).Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28AIM2 binds dsDNAAIM2 binds dsDNAAIM2 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). Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 8740881deoxyribonucleic acid [ChEBI:16991]deoxyribonucleic acidDesoxyribonukleinsaeure(Deoxyribonucleotide)n+m(Deoxyribonucleotide)mthymus nucleic acidDNAdeoxyribonucleic acidsDNAnDNSdesoxyribose nucleic acid(Deoxyribonucleotide)nDNAn+1ChEBI16991Reactome DB_ID: 8741111UniProt:O14862 AIM2AIM2AIM2FUNCTION 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 (By similarity). Tumor suppressor which may act by repressing NF-kappa-B transcriptional activity.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. Interacts with PYCARD, IFI16, EIF2AK2/PKR and MAPRE1. Interacts with PYDC5; disrupts assembly of the ALR inflammasome complex (PubMed:24531343).TISSUE SPECIFICITY Expressed in spleen, small intestine, peripheral blood leukocytes, and testis.INDUCTION By IFNG/IFN-gamma and IFNB1/IFN-beta.DOMAIN The pyrin domain mediates homotypic interaction with PYCARD (PubMed:19158676, PubMed:19158675).DOMAIN The HIN-20 domain mediates dsDNA binding via electrostatic interactions.MISCELLANEOUS Defects in AIM2 may be a cause of microsatellite unstable colon cancers.SIMILARITY Belongs to the HIN-200 family.UniProtO148621EQUAL343EQUALReactome DB_ID: 8740961dsDNA:AIM2 [cytosol]dsDNA:AIM2Reactome DB_ID: 8740881Reactome DB_ID: 87411111EQUAL343EQUALReactome Database ID Release 75874096Database 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=874096ReactomeR-HSA-8740961Reactome 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-HSA-874096.1Reactome Database ID Release 75844619Database 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=844619ReactomeR-HSA-8446191Reactome 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-HSA-844619.119158675Pubmed2009AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASCHornung, VAblasser, ACharrel-Dennis, MBauernfeind, FGHorvath, GCaffrey, DRLatz, EFitzgerald, Katherine ANature 458:514-818288107Pubmed2008The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune responseMuruve, DAPétrilli, VZaiss, AKWhite, LRClark, SARoss, PJParks, RJTschopp, JürgNature 452:103-719158676Pubmed2009AIM2 activates the inflammasome and cell death in response to cytoplasmic DNAFernandes-Alnemri, TYu, JWDatta, PWu, JAlnemri, ESNature 458:509-1319158679Pubmed2009An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasomeBurckstummer, TilmannBaumann, CBluml, StephanDixit, EDurnberger, GerhardJahn, HPlanyavsky, MBilban, MColinge, JBennett, KLSuperti-Furga, GNat Immunol 10:266-72AIM2 oligomerizesAIM2 oligomerizesAIM2 oligomerizes, forming AIM2 clusters that are able to interact with ASC (Fernandes-Alnemri et al. 2009, Hornung et al. 2009). The extent of oligomerization required is unknown.Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 8740961Reactome DB_ID: 12964241dsDNA:AIM2 oligomer [cytosol]dsDNA:AIM2 oligomerReactome Database ID Release 75874079Database 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=874079ReactomeR-HSA-8740791Reactome 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-HSA-874079.1dsDNA:AIM2 clusters bind ASCdsDNA:AIM2 clusters bind ASCdsDNA:AIM2 clusters bind ASC via a PYD-PYD interaction.Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 12964241Reactome DB_ID: 56119111EQUAL195EQUALReactome DB_ID: 8740981dsDNA:AIM2 oligomer:ASC [cytosol]dsDNA:AIM2 oligomer:ASCReactome DB_ID: 12964241Reactome DB_ID: 56119111EQUAL195EQUALReactome Database ID Release 75874098Database 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=874098ReactomeR-HSA-8740981Reactome 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-HSA-874098.1Reactome Database ID Release 75844620Database 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=844620ReactomeR-HSA-8446201Reactome 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-HSA-844620.1dsDNA:AIM2:ASC cluster binds procaspase-1dsDNA:AIM2:ASC cluster binds procaspase-1The ASC CARD domain recruits procaspase-1 leading to autoactivation, generating caspase-1.Authored: Jupe, S, 2010-04-22Reviewed: Kufer, TA, 2011-04-28Reviewed: Rittinger, K, 2011-06-06Reviewed: Wong, Edmond, 2011-06-06Edited: Jupe, S, 2011-04-28Reactome DB_ID: 8740981Reactome DB_ID: 44869211EQUAL404EQUALReactome DB_ID: 8741001dsDNA:AIM2 oligomer:ASC:Procaspase-1 [cytosol]dsDNA:AIM2 oligomer:ASC:Procaspase-1Reactome DB_ID: 8740981Reactome DB_ID: 44869211EQUAL404EQUALReactome Database ID Release 75874100Database 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=874100ReactomeR-HSA-8741001Reactome 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-HSA-874100.1Reactome Database ID Release 75844618Database 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=844618ReactomeR-HSA-8446181Reactome 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-HSA-844618.1Reactome Database ID Release 75844615Database 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=844615ReactomeR-HSA-8446151Reactome 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-HSA-844615.120098460Pubmed2010Intracellular DNA recognitionHornung, VLatz, ENat Rev Immunol 10:123-3020351692Pubmed2010The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA virusesRathinam, VAJiang, ZWaggoner, SNSharma, SCole, LEWaggoner, LVanaja, SKMonks, BGGanesan, SLatz, EHornung, VVogel, SNSzomolanyi-Tsuda, EFitzgerald, Katherine ANat Immunol 11:395-402Reactome Database ID Release 75622312Database 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=622312ReactomeR-HSA-6223121Reactome 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-HSA-622312.112620239Pubmed2003A unified model for apical caspase activationBoatright, KMRenatus, MScott, FLSperandio, SShin, HPedersen, IMRicci, JEEdris, WASutherlin, DPGreen, DRSalvesen, Guy S.Mol Cell 11:529-4117186029Pubmed2007Inflammasome adaptors and sensors: intracellular regulators of infection and inflammationMariathasan, SMonack, DMNat Rev Immunol 7:31-4019120479Pubmed2009Inflammasomes: guardians of cytosolic sanctityLamkanfi, MDixit, VMImmunol Rev 227:95-10517164409Pubmed2007Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory responseKummer, JABroekhuizen, REverett, HAgostini, LKuijk, LMartinon, FVan Bruggen, RTschopp, JürgJ Histochem Cytochem 55:443-5219302049Pubmed2009Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*)Masters, SLSimon, AAksentijevich, IKastner, DLAnnu Rev Immunol 27:621-6819120480Pubmed2009Function of Nod-like receptors in microbial recognition and host defenseFranchi, LWarner, NViani, KNunez, GImmunol Rev 227:106-2815162420Pubmed2004Mini-review: Specificity and expression of CIITA, the master regulator of MHC class II genesLeibundGut-Landmann, SWaldburger, JMKrawczyk, MOtten, LASuter, TFontana, AAcha-Orbea, HansReith, WEur J Immunol 34:1513-25