BioPAX pathway converted from "Trafficking and processing of endosomal TLR" in the Reactome database. Trafficking and processing of endosomal TLR Trafficking and processing of endosomal TLR This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> TLR folding by chaperones GP96 and CNPY3 TLR folding by chaperones GP96 and CNPY3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10296922 2 endoplasmic reticulum membrane GO 0005789 TLR7/8/9 [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PRPS2 [endoplasmic reticulum membrane] TLR9 [endoplasmic reticulum membrane] Reactome http://www.reactome.org Sus scrofa NCBI Taxonomy 9823 UniProt A0A287AR04 UniProt Q5I2M3 Reactome DB_ID: 10296926 2 endoplasmic reticulum lumen GO 0005788 UniProt:A5GFQ5 CNPY3 UniProt A5GFQ5 Chain Coordinates 31 EQUAL 278 EQUAL Reactome DB_ID: 10296932 1 Apo-GP96 dimer [endoplasmic reticulum lumen] Apo-GP96 dimer Reactome DB_ID: 10296930 2 UniProt:F1SRK6 HSP90B1 UniProt F1SRK6 22 EQUAL 803 EQUAL Reactome Database ID Release 82 10296932 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296932 Reactome R-SSC-1678941 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1678941.1 Reactome DB_ID: 211579 2 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 10296934 1 ATP-bound Gp96 dimer:CNPY3:TLR7/8/9 [endoplasmic reticulum membrane] ATP-bound Gp96 dimer:CNPY3:TLR7/8/9 Reactome DB_ID: 10296926 2 31 EQUAL 278 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10296922 2 Reactome DB_ID: 10296930 2 22 EQUAL 803 EQUAL Reactome DB_ID: 211579 2 Reactome Database ID Release 82 10296934 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296934 Reactome R-SSC-1679076 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1679076.1 Reactome Database ID Release 82 10296936 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296936 Reactome R-SSC-1678923 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1678923.1 GP96 (also known as GRP94, HSP90b1), a paralogue of HSP90 in the endoplasmic reticulum, acts as a chaperone for some integrines and Toll-like receptors. Macrophages or B-cells from gp96 knockout mice have abrogated function of TLR2, 4, 5, 7 and 9, but not TLR3 (Yang Y et al 2007, Liu B and Li Z 2008, Staron M et al 2010). GP96 interacts with TLRs and integrines via its C-terminal hydrophobic domain, formed by residues 652-678 (Wu S et al 2012). GP96 functions as a V-shaped dimer in ATP-dependent manner, however it remains unclear how ATP hydrolysis-dependent conformational changes of GP96 are regulated (Li Z and Srivastava PK 1993).<p>GP96 forms a complex with co-chaperone CNPY3, also known as PRAT4A. GP96-CNPY3 promotes the proper post-translational ectodomain folding of TLRs, but not TLR3 (Liu B et al 2010). 18509083 Pubmed 2008 Endoplasmic reticulum HSP90b1 (gp96, grp94) optimizes B-cell function via chaperoning integrin and TLR but not immunoglobulin Liu, B Li, Z Blood 112:1223-30 19965672 Pubmed 2010 gp96, an endoplasmic reticulum master chaperone for integrins and Toll-like receptors, selectively regulates early T and B lymphopoiesis Staron, M Yang, Y Liu, B Li, J Shen, Y Zúñiga-Pflücker, JC Aguila, HL Goldschneider, I Li, Z Blood 115:2380-90 8344253 Pubmed 1993 Tumor rejection antigen gp96/grp94 is an ATPase: implications for protein folding and antigen presentation Li, Z Srivastava, PK EMBO J 12:3143-51 17275357 Pubmed 2007 Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages Yang, Y Liu, B Dai, J Srivastava, PK Zammit, DJ Lefrançois, L Li, Z Immunity 26:215-26 20865800 Pubmed 2010 Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone Liu, B Yang, Y Qiu, Z Staron, M Hong, F Li, Y Wu, S Li, Yunfeng Hao, B Bona, R Han, D Li, Z Nat Commun 1:79 22223641 Pubmed 2012 The Molecular Chaperone gp96/GRP94 Interacts With Toll-Like Receptors And Integrins Via Its C-Terminal Hydrophobic Domain Wu, S Hong, F Gewirth, D Guo, B Liu, B Li, Z J Biol Chem inferred by electronic annotation IEA GO IEA Folded full-length TLR7/8/9 dissociates from the GP96:CNPY3 complex Folded full-length TLR7/8/9 dissociates from the GP96:CNPY3 complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10296934 1 Reactome DB_ID: 211606 2 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 10296926 2 31 EQUAL 278 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10296912 1 folded FL-TLR7/8/9 [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 10296932 1 Reactome Database ID Release 82 10296956 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296956 Reactome R-SSC-1678944 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1678944.1 Folded TLR9 dissociates from GP96:CNPY3 complex (Liu B et al 2010) and translocates to the endolysosome with the aid of the membrane protein UNC93b. Here we assume that TLR7 and TLR8 behave in a similar manner. inferred by electronic annotation IEA GO IEA Full-length TLR3/7/8/9 binds to UNC93B1 Full-length TLR3/7/8/9 binds to UNC93B1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10296912 1 Reactome DB_ID: 10296916 1 UniProt:A0A5G2QDN8 UNC93B1 UniProt A0A5G2QDN8 1 EQUAL 597 EQUAL Reactome DB_ID: 10296918 1 intracellular TLR:UNC93B1 [endoplasmic reticulum membrane] intracellular TLR:UNC93B1 Converted from EntitySet in Reactome Reactome DB_ID: 10296912 1 Reactome DB_ID: 10296916 1 1 EQUAL 597 EQUAL Reactome Database ID Release 82 10296918 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296918 Reactome R-SSC-1678926 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1678926.1 Reactome Database ID Release 82 10296920 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296920 Reactome R-SSC-1678921 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1678921.1 Mammalian UNC93B1, a multi-transmembrane protein, directly associates with transmembrane domains of TLR3, TLR7, TLR8 and TLR9 (and mouse TLR13) in the ER and facilitates their translocation to endolysosome compartments (Brinkmann et al 2007; Kim et al 2008; Itoh H et al 2011). Mutant mouse and human cells that lack functional UNC93B1 showed disrupted signaling via the endosomal TLRs (Taneda K et al 2006; Fukui et al 2009; Kim YM et al 2008; Qi R et al 2010; Koehn J et al 2007). Furthermore, defects in the human gene encoding UNC93B1 are associated with the increased susceptibility to herpes simplex encephalitis (HSE) in children (Casrouge A et al 2006).<p>TLR7 and TLR9 compete for UNC931-dependent trafficking and under normal circumstances TLR9 predominates over TLR7. This preference for TLR9 is mediated by an N-terminal domain in UNC93B1 and is reversed to TLR7 if UNC93B1 loses the preferential N-terminal binding site via mutation of aspartate at position 34. Loss of binding to TLR9 and preferential association with TLR7 resulted in hyperresponsiveness to RNA ligands (Fukui et al 2009).<p>TLR3 appears to translocate to the endosomal compartment with equal efficiency regardless of the presence or absence of the N-terminal domain that mediates preference for TLR9. Thus, endosomal TLR trafficking is orchestrated by UNC93B1 which determines how efficiently each TLR is able to move from the ER to the endolysosomes to initiate host responses. 20855885 Pubmed 2010 Secretion of the human Toll-like receptor 3 ectodomain is affected by single nucleotide polymorphisms and regulated by Unc93b1 Qi, R Hoose, S Schreiter, J Sawant, KV Lamb, R Ranjith-Kumar, CT Mills, J San Mateo, L Jordan, JL Kao, CC J Biol Chem 285:36635-44 16415873 Pubmed 2006 The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9 Tabeta, K Hoebe, K Janssen, EM Du, X Georgel, P Crozat, K Mudd, S Mann, N Sovath, S Goode, J Shamel, L Herskovits, AA Portnoy, DA Cooke, M Tarantino, LM Wiltshire, T Steinberg, BE Grinstein, S Beutler, B Nat Immunol 7:156-64 17452530 Pubmed 2007 The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling Brinkmann, MM Spooner, E Hoebe, K Beutler, B Ploegh, HL Kim, YM J Cell Biol 177:265-75 18305481 Pubmed 2008 UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes Kim, YM Brinkmann, MM Paquet, ME Ploegh, HL Nature 452:234-8 18082565 Pubmed 2007 Assessing the function of human UNC-93B in Toll-like receptor signaling and major histocompatibility complex II response Koehn, J Huesken, D Jaritz, M Rot, A Zurini, M Dwertmann, A Beutler, B Korthäuer, U Hum Immunol 68:871-8 16973841 Pubmed 2006 Herpes simplex virus encephalitis in human UNC-93B deficiency Casrouge, A Zhang, SY Eidenschenk, C Jouanguy, E Puel, A Yang, K Alcais, A Picard, C Mahfoufi, N Nicolas, N Lorenzo, L Plancoulaine, S Sénéchal, B Geissmann, F Tabeta, K Hoebe, K Du, X Miller, RL Héron, B Mignot, C de Villemeur, TB Lebon, Pierre Dulac, O Rozenberg, F Beutler, B Tardieu, M Abel, L Casanova, JL Science 314:308-12 22164301 Pubmed 2011 UNC93B1 physically associates with human TLR8 and regulates TLR8-mediated signaling Itoh, Hiroki Tatematsu, Megumi Watanabe, Ayako Iwano, Katsunori Funami, K Seya, T Matsumoto, M PLoS ONE 6:e28500 19451267 Pubmed 2009 Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing Fukui, R Saitoh, S Matsumoto, F Kozuka-Hata, H Oyama, M Tabeta, K Beutler, B Miyake, K J Exp Med 206:1339-50 inferred by electronic annotation IEA GO IEA Endosomal TLRs pass through the Golgi Endosomal TLRs pass through the Golgi This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10296918 1 Reactome DB_ID: 10296954 1 Golgi membrane GO 0000139 intracellular TLR:UNC93B1 [Golgi membrane] intracellular TLR:UNC93B1 Converted from EntitySet in Reactome Reactome DB_ID: 10296950 1 TLR3/7/8/9 [Golgi membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 10296952 1 1 EQUAL 597 EQUAL Reactome Database ID Release 82 10296954 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296954 Reactome R-SSC-1679067 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1679067.1 Reactome Database ID Release 82 10296969 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296969 Reactome R-SSC-1678998 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1678998.1 TLRs traffic through the Golgi complex by the conventional secretory pathway and are routed to endolysosomes where they bind their ligands (Chockalingam A et al 2008, Ewald SE et al 2011). . 19079358 Pubmed 2009 TLR9 traffics through the Golgi complex to localize to endolysosomes and respond to CpG DNA Chockalingam, A Brooks, JC Cameron, JL Blum, LK Leifer, CA Immunol Cell Biol 87:209-17 21402738 Pubmed 2011 Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase Ewald, SE Engel, A Lee, J Wang, M Bogyo, M Barton, GM J Exp Med 208:643-51 inferred by electronic annotation IEA GO IEA 3.4.22.41 3.4.22.40 3.4.22.34 3.4.22.8 3.4.22.28 3.4.22.16 3.4.22.27 3.4.22.38 3.4.22.1 3.4.22.15 3.4.22.14 TLR processing at low pH TLR processing at low pH This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10296869 1 endolysosome membrane GO 0036020 FL-TLR9 dimer [endolysosome membrane] FL-TLR9 dimer Reactome DB_ID: 10296867 2 UniProt:Q5I2M3 26 EQUAL 1032 EQUAL Reactome Database ID Release 82 10296869 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296869 Reactome R-SSC-1679073 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1679073.1 Reactome DB_ID: 10296865 1 FL-TLR7 dimer [endolysosome membrane] FL-TLR7 dimer Reactome DB_ID: 10296863 2 UniProt:A0A287AR04 PRPS2 27 EQUAL 1049 EQUAL Reactome Database ID Release 82 10296865 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296865 Reactome R-SSC-188168 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-188168.1 Reactome DB_ID: 10296873 1 C-ter-TLR9 dimer [endolysosome membrane] C-ter-TLR9 dimer Reactome DB_ID: 10296871 2 1 EQUAL 1032 EQUAL Reactome Database ID Release 82 10296873 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296873 Reactome R-SSC-1678956 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1678956.1 Reactome DB_ID: 10296877 1 C-ter TLR7 dimer [endolysosome membrane] C-ter TLR7 dimer Reactome DB_ID: 10296875 2 1 EQUAL 1049 EQUAL Reactome Database ID Release 82 10296877 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296877 Reactome R-SSC-1678924 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1678924.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10296893 endolysosome lumen GO 0036021 Legumain/Cathepsins [endolysosome lumen] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CTSK [endolysosome lumen] CTSB [endolysosome lumen] CTSS [endolysosome lumen] LGMN [endolysosome lumen] UniProt Q9GLE3 UniProt A1E295 UniProt F1SS93 UniProt F1SD70 GO 0004197 GO molecular function Reactome Database ID Release 82 10296894 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296894 Reactome Database ID Release 82 10296896 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296896 Reactome R-SSC-1678920 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1678920.1 Endosome maturation (acidification) is required for both the activation of TLR9 and TLR7 through proteolytic cleavage and the disassembly of pathogens, thereby releasing the TLR ligands within them. TLR7 and TLR9 are cleaved within their ectodomains by pH-sensitive cysteine endopeptidases. Cathepsins (CTS) B, K, L, and S, and asparagine endopeptidase (AEP, also known as legumain) have been implicated in endolysosomal TLR processing, however, several groups have reported somewhat controversial results on the role of specific proteases (Matsumoto F et al 2008, Park B et al 2008, Ewald SE et al 2008, Ewald SE et al 2011, Sepulveda FE et al 2009).<p>One study showed that TLR9 proteolysis is a multistep process with the initial cleavage that can be mediated by AEP or multiple members of the cathepsin family. The second event is mediated exclusively by cathepsins. TLR7 and TLR3 were reported to be cleaved in a similar manner (Ewald SE et al 2011). Cleavage of TLR3 is not shown in this reaction, since other studies demonstrated that the N-terminal region of TLR3 ectodomain was implicated in ligand binding, suggesting that TLR3 may function as a full-length receptor (Liu L et al 2008, Tokisue T et al 2008).</p> <p>Both full-length receptor and cleaved fragment corresponding to the C-terminal part of TLR9 were capable to bind ligand, however only the processed form (TLR9 C-ter, aa 471-1032) was shown to bind MyD88 and induce signaling in different mouse cells (Ewald SE et al 2008). 18166152 Pubmed 2008 Cathepsins are required for Toll-like receptor 9 responses Matsumoto, F Saitoh, S Fukui, R Kobayashi, T Tanimura, N Konno, K Kusumoto, Y Akashi-Takamura, S Miyake, K Biochem Biophys Res Commun 367:693-9 18931679 Pubmed 2008 Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9 Park, B Brinkmann, MM Spooner, E Lee, CC Kim, YM Ploegh, HL Nat Immunol 9:1407-14 18820679 Pubmed 2008 The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor Ewald, SE Lee, BL Lau, L Wickliffe, KE Shi, GP Chapman, HA Barton, GM Nature 456:658-62 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 82 2134525 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2134525 Reactome R-HSA-2134525 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2134525.1 Reactome DB_ID: 9631150 hydron [ChEBI:15378] hydron ChEBI 15378 3.4.22.41 3.4.22.40 3.4.22.34 3.4.22.8 3.4.22.28 3.4.22.16 3.4.22.27 3.4.22.38 3.4.22.1 3.4.22.15 3.4.22.14 TLR9 processing at neutral pH TLR9 processing at neutral pH This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10296869 1 Reactome DB_ID: 10296960 1 N-ter TLR9 dimer [endolysosome membrane] N-ter TLR9 dimer Reactome DB_ID: 10296958 2 Reactome Database ID Release 82 10296960 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296960 Reactome R-SSC-1679007 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1679007.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10296964 CTSS-like proteins [endolysosome lumen] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CTSS [endolysosome lumen] Reactome Database ID Release 82 10296965 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296965 Reactome Database ID Release 82 10296967 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296967 Reactome R-SSC-1678981 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1678981.1 TLR9 traffics to an endosomal vesicle where it is processed by cathepsin S at neural pH to generate an N-terminal product (TLR9 N-ter, aa 1-723). The N-terminal fragment of TLR9 also binds ligand, but in contrast to the C-terminal fragment it inhibits TLR9 signaling. Thus, a proper balance between the two proteolytic events probably regulates TLR9-mediated host responses. (Chockalingam A et al 2011). 21604257 Pubmed 2011 Negative regulation of signaling by a soluble form of toll-like receptor 9 Chockalingam, A Cameron, JL Brooks, JC Leifer, CA Eur J Immunol 41:2176-84 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10351678 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10351678 Reactome R-SSC-1679131 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1679131.1 Mammalian TLR3, TLR7, TLR8, TLR9 are endosomal receptors that sense nucleic acids that have been released from endocytosed/phagocytosed bacteria, viruses or parasites. These TLRs have a ligand-recognition domain that faces the lumen of the endosome (which is topologically equivalent to the outside of the cell), a transmembrane domain, and a signaling domain that faces the cytosol.<p>Under normal conditions, self nucleic acids are not recognized by TLRs due to multiple levels of regulation including receptor compartmentalization, trafficking and proteolytic processing (Barton GM et al 2006, Ewald SE et al 2008). At steady state TLR3, TLR7, TLR8, TLR9 reside primarily in the endoplasmic reticulum (ER), however, their activation by specific ligands only occurs within acidified endolysosomal compartments (Hacker H et al 1998, Funami K et al 2004, Gibbard RJ et al 2006). Several chaperon proteins associate with TLRs in the ER to provide efficient translocation to endolysosome. Upon reaching endolysosomal compartments the ectodomains of TLR7 and TLR9 are proteolytically cleaved by cysteine endoproteases. Both full-length and cleaved C-terminus of TLR9 bind CpG-oligodeoxynucleotides, however it has been proposed that only the processed receptor is functional.<p> Although similar cleavage of TLR3 has been reported by Ewald et al 2011, other studies demonstrated that the N-terminal region of TLR3 ectodomain was implicated in ligand binding, thus TLR3 may function as a full-length receptor (Liu L et al 2008, Tokisue T et al 2008).<p> There are no data on TLR8 processing, although the cell biology of TLR8 is probably similar to TLR9 and TLR7 (Gibbard RJ et al 2006, Wei T et al 2009). 9799232 Pubmed 1998 CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation Hacker, H Mischak, H Miethke, T Liptay, S Schmid, R Sparwasser, T Heeg, K Lipford, GB Wagner, H EMBO J 17:6230-40 16144834 Pubmed 2005 Recognition of double-stranded RNA by human toll-like receptor 3 and downstream receptor signaling requires multimerization and an acidic pH de Bouteiller, O Merck, E Hasan, UA Hubac, S Benguigui, B Trinchieri, G Bates, EE Caux, C J Biol Chem 280:38133-45 16341217 Pubmed 2006 Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA Barton, GM Kagan, JC Medzhitov, R Nat Immunol 7:49-56 19521997 Pubmed 2009 Homology modeling of human Toll-like receptors TLR7, 8, and 9 ligand-binding domains Wei, T Gong, J Jamitzky, F Heckl, WM Stark, RW Rössle, SC Protein Sci 18:1684-91 15226270 Pubmed 2004 The cytoplasmic 'linker region' in Toll-like receptor 3 controls receptor localization and signaling Funami, K Matsumoto, M Oshiumi, H Akazawa, T Yamamoto, A Seya, T Int Immunol 16:1143-54 18776324 Pubmed 2008 Significance of the N-terminal histidine-rich region for the function of the human toll-like receptor 3 ectodomain Tokisue, T Watanabe, T Tsujita, T Nishikawa, S Hasegawa, T Seya, T Matsumoto, M Fukuda, K Nucleic Acids Symp Ser (Oxf)203-4 18420935 Pubmed 2008 Structural basis of toll-like receptor 3 signaling with double-stranded RNA Liu, L Botos, I Wang, Y Leonard, JN Shiloach, J Segal, DM Davies, DR Science 320:379-81 16857668 Pubmed 2006 Conserved features in the extracellular domain of human toll-like receptor 8 are essential for pH-dependent signaling Gibbard, RJ Morley, PJ Gay, Nicholas J J Biol Chem 281:27503-11 inferred by electronic annotation IEA GO IEA