BioPAX pathway converted from "MyD88 oligomerization within the complex of activated TLR 7/8 or 9 : MyD88" in the Reactome database. LEFT-TO-RIGHT MyD88 oligomerization within the complex of activated TLR 7/8 or 9 : MyD88 Structural analysis of MyD88:IRAK4 and MyD88:IRAK4:IRAK2 suggested that upon MyD88 recruitment to an activated dimerized TLR the MyD88 death domains clustering induces the formation of Mydosome, a large oligomeric signaling platform (Motshwene PG et al 2009, Lin SC et al 2010). Assembly of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. The oligomer complex stoichiometry was reported as 7:4 and 8:4 for MyD88:IRAK4 (Motshwene PG et al 2009), and 6:4:4 in the complex of MyD88:IRAK4:IRAK2(Lin SC et al 2010). Authored: Shamovsky, V, 2010-09-22 Reviewed: Gillespie, ME, 2010-10-29 Edited: Shamovsky, V, 2010-11-15 MyD88 complexed with the activated TLR receptor Reactome DB_ID: 975124 endosome membrane GENE ONTOLOGY GO:0010008 MYD88 homodimer Reactome DB_ID: 975152 MYD88 MyD88 Reactome DB_ID: 975123 UniProt:Q99836 MYD88 MYD88 FUNCTION Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response (PubMed:15361868, PubMed:18292575, PubMed:33718825). Acts via IRAK1, IRAK2, IRF7 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:15361868, PubMed:24316379, PubMed:19506249). Increases IL-8 transcription (PubMed:9013863). Involved in IL-18-mediated signaling pathway. Activates IRF1 resulting in its rapid migration into the nucleus to mediate an efficient induction of IFN-beta, NOS2/INOS, and IL12A genes. Upon TLR8 activation by GU-rich single-stranded RNA (GU-rich RNA) derived from viruses such as SARS-CoV-2, SARS-CoV and HIV-1, induces IL1B release through NLRP3 inflammasome activation (PubMed:33718825). MyD88-mediated signaling in intestinal epithelial cells is crucial for maintenance of gut homeostasis and controls the expression of the antimicrobial lectin REG3G in the small intestine (By similarity).SUBUNIT Homodimer. Also forms heterodimers with TIRAP. Binds to TLR2, TLR4, TLR5, IRAK1, IRAK2 and IRAK4 via their respective TIR domains. Interacts with IL18R1. Interacts with BMX, IL1RL1, IKBKE and IRF7. Interacts with LRRFIP1 and LRRFIP2; this interaction positively regulates Toll-like receptor (TLR) signaling in response to agonist. Interacts with FLII. LRRFIP1 and LRRFIP2 compete with FLII for MYD88-binding. Interacts with IRF1. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and TRAF6; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. May interact with PIK3AP1. Interacts (via TIR domain) with DHX9 (via H2A and OB-fold regions); this interaction is direct (PubMed:20696886). Interacts with OTUD4 deubiquitinase; the interaction is direct (PubMed:29395066).SUBUNIT (Microbial infection) In case of infection, interacts with uropathogenic E.coli protein TcpC; suppressing Toll-like receptor (TLR)-mediated cytokine production.SUBUNIT (Microbial infection) In case of infection, interacts with uropathogenic E.faecalis protein TcpF; suppressing Toll-like receptor (TLR)-mediated cytokine production.TISSUE SPECIFICITY Ubiquitous.DOMAIN The intermediate domain (ID) is required for the phosphorylation and activation of IRAK.PTM Ubiquitinated; undergoes 'Lys-63'-linked polyubiquitination. OTUD4 specifically hydrolyzes 'Lys-63'-linked polyubiquitinated MYD88.DISEASE Defects in MYD88 are frequently found in many hematological malignancies, such as activated B-cell type diffuse large B-cell lymphoma (ABC-DLBCL), cutaneous diffuse large B cell lymphoma (CBCL) and primary central nervous system lymphoma (PCNSL). Homo sapiens NCBI Taxonomy 9606 UniProt Q99836 1 EQUAL 296 EQUAL Reactome Database ID Release 81 975123 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=975123 Reactome R-HSA-975123 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-975123.1 Reactome http://www.reactome.org 2 Reactome Database ID Release 81 975152 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=975152 Reactome R-HSA-975152 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-975152.1 1 Converted from EntitySet in Reactome Activated TLR7-9 homodimers Reactome DB_ID: 975158 C-ter TLR7 dimer:TLR7, TLR8 ligands Reactome DB_ID: 188132 C-ter TLR7 dimer C-terminus TLR7 dimer Reactome DB_ID: 1679575 C-ter TLR7 TLR7(?-1049) processed TLR7 Toll Like Receptor 7 (TLR 7) Reactome DB_ID: 1679579 UniProt:Q9NYK1 TLR7 TLR7 UNQ248/PRO285 FUNCTION Endosomal receptor that plays a key role in innate and adaptive immunity (PubMed:14976261, PubMed:32433612). Controls host immune response against pathogens through recognition of uridine-containing single strand RNAs (ssRNAs) of viral origin or guanosine analogs (PubMed:31608988, PubMed:27742543, PubMed:12738885, PubMed:32706371). Upon binding to agonists, undergoes dimerization that brings TIR domains from the two molecules into direct contact, leading to the recruitment of TIR-containing downstream adapter MYD88 through homotypic interaction (PubMed:27742543). In turn, the Myddosome signaling complex is formed involving IRAK4, IRAK1, TRAF6, TRAF3 leading to activation of downstream transcription factors NF-kappa-B and IRF7 to induce proinflammatory cytokines and interferons, respectively (PubMed:27742543, PubMed:32706371).ACTIVITY REGULATION Activated by guanosine analogs including deoxyguanosine, 7-thia-8-oxoguanosine or 7-deazaguanosine in a RNA-independent manner. Activated by imiquimod (PubMed:32706371).SUBUNIT Homodimer (PubMed:27742543). Interacts with MYD88 via their respective TIR domains (Probable). Interacts with UNC93B1 (PubMed:33432245). Interacts with SMPDL3B (By similarity).TISSUE SPECIFICITY Detected in brain, placenta, spleen, stomach, small intestine, lung and in plasmacytoid pre-dendritic cells. Expressed in peripheral mononuclear blood cells (PubMed:32706371).DOMAIN Contains two binding domains, first site for small ligands and second site for ssRNA.SIMILARITY Belongs to the Toll-like receptor family. UniProt Q9NYK1 1 EQUAL 1049 EQUAL Reactome Database ID Release 81 1679579 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=1679579 Reactome R-HSA-1679579 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-1679579.1 2 Reactome Database ID Release 81 1679575 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=1679575 Reactome R-HSA-1679575 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-1679575.1 1 Converted from EntitySet in Reactome TLR7, TLR8 ligands Ligands recognized by TLR7 and TLR8 Reactome DB_ID: 9684904 Converted from EntitySet in Reactome GU-rich ssRNA Reactome DB_ID: 9684903 SARS-CoV-1 GU-rich ssRNA Reactome DB_ID: 9684906 endosome lumen GENE ONTOLOGY GO:0031904 Reactome Database ID Release 81 9684906 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=9684906 Reactome R-COV-9684906 2 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-COV-9684906.2 ChEBI 33697 additional information MI MI:0361 HIV1 GU-rich ssRNA Reactome DB_ID: 9684900 Reactome Database ID Release 81 9684900 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=9684900 Reactome R-HIV-9684900 2 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-HIV-9684900.2 ChEBI 33697 Influenza GU-rich ssRNA Reactome DB_ID: 9684905 Reactome Database ID Release 81 9684905 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=9684905 Reactome R-FLU-9684905 2 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-FLU-9684905.2 ChEBI 33697 SARS-CoV-2 GU-rich ssRNA Reactome DB_ID: 9754729 Reactome Database ID Release 81 9754729 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=9754729 Reactome R-COV-9754729 3 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-COV-9754729.3 ChEBI 33697 Reactome Database ID Release 81 9684903 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=9684903 Reactome R-NUL-9684903 8 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-NUL-9684903.8 Converted from EntitySet in Reactome Imidazoquinoline compounds Reactome DB_ID: 188128 R-848 resiquimod Reactome DB_ID: 188126 resiquimod [ChEBI:36706] resiquimod ChEBI CHEBI:36706 Reactome Database ID Release 81 188126 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=188126 Reactome R-ALL-188126 4 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-ALL-188126.4 IMIQ imiquimod Reactome DB_ID: 188127 imiquimod [ChEBI:36704] imiquimod ChEBI CHEBI:36704 Reactome Database ID Release 81 188127 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=188127 Reactome R-ALL-188127 4 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-ALL-188127.4 Reactome Database ID Release 81 188128 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=188128 Reactome R-ALL-188128 2 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-ALL-188128.2 Reactome Database ID Release 81 9684904 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=9684904 Reactome R-NUL-9684904 8 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-NUL-9684904.8 1 Reactome Database ID Release 81 188132 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=188132 Reactome R-HSA-188132 4 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-188132.4 C-ter TLR9 dimer:unmethylated CpG DNA Reactome DB_ID: 1679087 Unmethylated CpG DNA Reactome DB_ID: 167913 Reactome Database ID Release 81 167913 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=167913 Reactome R-ALL-167913 3 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-ALL-167913.3 ChEBI 61120 1 C-ter-TLR9 dimer C-terminus Toll like receptor 9 (TLR9) dimer Reactome DB_ID: 1679581 TLR9(?-1032) TLR9 C-terminus processed Toll Like Receptor 9 Reactome DB_ID: 1679580 UniProt:Q9NR96 TLR9 TLR9 UNQ5798/PRO19605 FUNCTION Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR9 is a nucleotide-sensing TLR which is activated by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:11564765, PubMed:17932028). Controls lymphocyte response to Helicobacter infection (By similarity). Upon CpG stimulation, induces B-cell proliferation, activation, survival and antibody production (PubMed:23857366).SUBUNIT Monomer and homodimer. Exists as a monomer in the absence of unmethylated cytidine-phosphate-guanosine (CpG) ligand. Proteolytic processing of an insertion loop (Z-loop) is required for homodimerization upon binding to the unmethylated CpG ligand leading to its activation (By similarity). Interacts with MYD88 via their respective TIR domains (By similarity). Interacts with BTK (PubMed:17932028). Interacts (via transmembrane domain) with UNC93B1. Interacts with CD300LH; the interaction may promote full activation of TLR9-triggered innate responses (By similarity). Interacts with CNPY3 and HSP90B1; this interaction is required for proper folding in the endoplasmic reticulum (PubMed:20865800). Interacts with SMPDL3B (By similarity).TISSUE SPECIFICITY Highly expressed in spleen, lymph node, tonsil and peripheral blood leukocytes, especially in plasmacytoid pre-dendritic cells. Levels are much lower in monocytes and CD11c+ immature dendritic cells. Also detected in lung and liver.PTM Activated by proteolytic cleavage of the flexible loop between repeats LRR14 and LRR15 within the ectodomain. Cleavage requires UNC93B1. Proteolytically processed by first removing the majority of the ectodomain by either asparagine endopeptidase (AEP) or a cathepsin followed by a trimming event that is solely cathepsin mediated and required for optimal receptor signaling.SIMILARITY Belongs to the Toll-like receptor family. UniProt Q9NR96 1 EQUAL 1032 EQUAL Reactome Database ID Release 81 1679580 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=1679580 Reactome R-HSA-1679580 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-1679580.1 2 Reactome Database ID Release 81 1679581 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=1679581 Reactome R-HSA-1679581 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-1679581.1 1 Reactome Database ID Release 81 1679087 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=1679087 Reactome R-HSA-1679087 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-1679087.1 Reactome Database ID Release 81 975158 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=975158 Reactome R-HSA-975158 3 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-975158.3 1 Reactome Database ID Release 81 975124 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=975124 Reactome R-HSA-975124 3 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-975124.3 MYD88 MyD88 Reactome DB_ID: 166059 cytosol GENE ONTOLOGY GO:0005829 1 EQUAL 296 EQUAL Reactome Database ID Release 81 166059 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=166059 Reactome R-HSA-166059 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-166059.1 4 oligo-MyD88:activated TLR7-9 Reactome DB_ID: 975114 MyD88 oligomer Reactome DB_ID: 975141 6 Reactome Database ID Release 81 975141 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=975141 Reactome R-HSA-975141 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-975141.1 1 1 Reactome Database ID Release 81 975114 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=975114 Reactome R-HSA-975114 3 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-975114.3 Reactome Database ID Release 81 975098 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=975098 Reactome R-HSA-975098 3 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-975098.3 20485341 Pubmed 2010 Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling Lin, SC Lo, YC Wu, H Nature 465:885-90 20966070 Pubmed 2011 Two human MYD88 variants, S34Y and R98C, interfere with MyD88-IRAK4-myddosome assembly George, Julie Motshwene, Precious G Wang, Hui Kubarenko, Andriy V Rautanen, Anna Mills, Tara C Hill, Adrian V S Gay, Nicholas J Weber, Alexander N R J. Biol. Chem. 286:1341-53 19592493 Pubmed 2009 An oligomeric signaling platform formed by the Toll-like receptor signal transducers MyD88 and IRAK-4 Motshwene, PG Moncrieffe, MC Grossmann, JG Kao, C Ayaluru, M Sandercock, AM Robinson, CV Latz, E Gay, Nicholas J J Biol Chem 284:25404-11