MYD88 (myeloid differentiation primary response protein 88) is a cytosolic signaling adaptor of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families. It has an N-terminal death domain, a short intermediate domain and a C-terminal TIR domain. Ligand-activated TLRs (all except TLR3) and IL-1, IL-18, IL-33 and IL-36 receptors recruit MYD88 through TIR-TIR contacts, either directly or via the bridging adaptor TIRAP at the plasma membrane (TLR2, TLR4). At endosomes it serves TLR7, TLR8 and TLR9. MYD88 death domains then oligomerise and recruit IRAK4 and IRAK1/IRAK2 into a helical signaling platform, the Myddosome. In the Myddosome IRAK4 is activated and TRAF6 is engaged, which leads to NF-kappa-B and MAP kinase activation, inflammatory cytokine production and, in plasmacytoid dendritic cells, IRF7-dependent type I interferon production. MYD88 has no known enzymatic activity. It is regulated by K63- and K11-linked ubiquitination and by deubiquitinases such as USP3 and OTUD5. Inherited MYD88 deficiency causes susceptibility to pyogenic bacterial infection. The recurrent somatic L265P mutation constitutively activates the pathway in B-cell lymphomas.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002224 toll-like receptor signaling pathway | NAS PMID:38961291 Molecular definition of the endogenous Toll-like receptor si... | ACCEPT | Summary: MYD88 is the principal signaling adaptor of all TLRs except TLR3; the endogenous-myddosome imaging study (NAS) places it in the TLR pathway. Reason: Correct and central. The more specific child GO:0002755 is also carried; this general term is consistent with it. Supporting Evidence: PMID:38961291 within most myddosomes, MyD88 forms barrel-like structures that function as scaffolds for effector protein recruitment. PMID:36865541 Signaling via most TLRs and IL-1Rs is mediated by the protein myeloid differentiation primary-response protein 88 (MyD88). |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based annotation (IPR017281, MyD88 family) to the MyD88-dependent TLR pathway. Reason: MYD88 defines this pathway: it is the adaptor that bridges TLR TIR domains to IRAK4 via its death domain. Correct and core. Supporting Evidence: PMID:9734363 We now demonstrate that signaling by the human Toll receptor employs an adaptor protein, MyD88, and induces activation of NF-kappaB via the Pelle-like kinase IRAK and the TRAF6 protein, similar to IL-1R-mediated NF-kappaB activation. PMID:36865541 Signaling via most TLRs and IL-1Rs is mediated by the protein myeloid differentiation primary-response protein 88 (MyD88). |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | NAS PMID:36865541 Regulation of innate immune signaling by IRAK proteins. | ACCEPT | Summary: Review-based (NAS) annotation to the MyD88-dependent TLR pathway. Reason: Core process for MYD88; the IRAK review describes MyD88 as the signaling adaptor for most TLRs. Supporting Evidence: PMID:36865541 Signaling via most TLRs and IL-1Rs is mediated by the protein myeloid differentiation primary-response protein 88 (MyD88). PMID:36865541 The myddosome is a supramolecular signaling complex assembled upon dimerization of IL-1Rs and most TLRs (except TLR3), and is composed of MyD88, IRAK4, IRAK1 and/or IRAK2, in addition to TRAF6. |
| GO:0005102 signaling receptor binding | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl ortholog transfer (rat) of generic signaling receptor binding. Reason: Correct but uninformative. MYD88 binds specific receptors: TLRs and IL-1 receptor family members through TIR-TIR contacts. The informative child is Toll-like receptor binding (also GO:0005149 interleukin-1 receptor binding, carried separately). Proposed replacements: Toll-like receptor binding Supporting Evidence: PMID:9430229 MyD88 binds to both IRAK (IL-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of IRAK with the receptor. PMID:17258210 We show that the TLR adaptor Mal is critical for linking Myeloid Differentiation primary response protein 88 (MyD88) to TLR2 and TLR4. |
| GO:0005121 Toll binding | IEA GO_REF:0000107 | MODIFY | Summary: Rat-sourced Ensembl transfer of GO:0005121 Toll binding. Reason: GO:0005121 is defined as binding to "a Toll protein"; GO keeps it distinct from GO:0035325 Toll-like receptor binding, and vertebrates have Toll-like receptors, not Toll. For human MYD88 the correct term is Toll-like receptor binding. This is the same Toll-versus-TLR conflation as the GO:0008063 rows. Proposed replacements: Toll-like receptor binding Supporting Evidence: PMID:17258210 We show that the TLR adaptor Mal is critical for linking Myeloid Differentiation primary response protein 88 (MyD88) to TLR2 and TLR4. PMID:15728506 we also demonstrated that TLR10 directly associates with MyD88, the common Toll IL-1 receptor domain adapter. |
| GO:0005123 death receptor binding | TAS PMID:9374458 IRAK (Pelle) family member IRAK-2 and MyD88 as proximal medi... | MODIFY | Summary: TAS from the Science 1997 paper showing MyD88 associates with the IL-1R signaling complex. Reason: GO:0005123 death receptor binding means binding a TNF-receptor-superfamily death receptor (Fas, TNFR1, DR4/5). The cited paper shows MyD88 association with the IL-1 receptor complex, not with a death receptor; the death domain of MyD88 binds IRAK death domains, which is a different relationship. Replace with interleukin-1 receptor binding. Proposed replacements: interleukin-1 receptor binding Supporting Evidence: PMID:9374458 Both associate with the IL-1R signaling complex. PMID:9430229 Here we show that MyD88, a previously described protein of unknown function, is recruited to the IL-1 receptor complex following IL-1 stimulation. |
| GO:0005126 cytokine receptor binding | IEA GO_REF:0000117 | MODIFY | Summary: ARBA-predicted cytokine receptor binding. Reason: Correct in spirit (IL-1R, IL-18R and IL-33R are cytokine receptors) but less specific than GO:0005149, which is supported experimentally. Proposed replacements: interleukin-1 receptor binding Supporting Evidence: PMID:36865541 Responses to these cytokines are mediated by the IL-1 receptor (IL-1R) and the closely related IL-18R and IL-33R, all of which employs MyD88 as signaling adaptor, similarly to TLRs PMID:9430229 Here we show that MyD88, a previously described protein of unknown function, is recruited to the IL-1 receptor complex following IL-1 stimulation. |
| GO:0005149 interleukin-1 receptor binding | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA transfer of interleukin-1 receptor binding. Reason: MYD88 is recruited to and binds the IL-1R1/IL-1RAcP complex through its C-terminal TIR domain. Supporting Evidence: PMID:9430229 MyD88 binds to both IRAK (IL-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of IRAK with the receptor. PMID:9430229 Here we show that MyD88, a previously described protein of unknown function, is recruited to the IL-1 receptor complex following IL-1 stimulation. |
| GO:0005515 protein binding | IPI PMID:10880445 The apoptotic signaling pathway activated by Toll-like recep... | MODIFY | Summary: MyD88 binds FADD (co-IP) in TLR2-induced apoptosis. Reason: Binding to FADD is a death-domain to death-domain interaction; GO:0070513 death domain binding is informative. Apoptotic signalling via FADD is a minor, overexpression-driven output. Proposed replacements: death domain binding Supporting Evidence: PMID:10880445 Moreover, MyD88 binds FADD and is sufficient to induce apoptosis. PMID:10880445 TLR2 signals for apoptosis through MyD88 via a pathway involving Fas-associated death domain protein (FADD) and caspase 8. |
| GO:0005515 protein binding | IPI PMID:11544529 Mal (MyD88-adapter-like) is required for Toll-like receptor-... | MODIFY | Summary: MyD88 heterodimerises with Mal/TIRAP. Reason: The MyD88-TIRAP interaction is TIR-TIR; replace protein binding with TIR domain binding. Proposed replacements: TIR domain binding Supporting Evidence: PMID:11544529 Mal can form homodimers and can also form heterodimers with MyD88. |
| GO:0005515 protein binding | IPI PMID:12860405 Characterization of Pellino2, a substrate of IRAK1 and IRAK4... | MODIFY | Summary: Interaction with IRAK4 reported in the Pellino2 study (abstract only cached). Reason: MyD88-IRAK4 binding is well established and is the step that recruits the kinase to the receptor. Protein kinase binding is more informative than protein binding; the full text was not available so the precise domain evidence is deferred to the curator. Proposed replacements: protein kinase binding Supporting Evidence: PMID:12860405 In an attempt to discover novel signal transducers in TIR signaling, we identified human Pellino2 as an interaction partner of IRAK4. PMID:36865541 in a stoichiometry of 6 to 8 molecules of MyD88 to 4 molecules of IRAK4. |
| GO:0005515 protein binding | IPI PMID:15728506 Human TLR10 is a functional receptor, expressed by B cells a... | MODIFY | Summary: Interaction with a TLR (partner recorded as TLR4) in the TLR10 characterisation paper. Reason: The paper shows direct TLR-MyD88 association; Toll-like receptor binding is the informative MF. Proposed replacements: Toll-like receptor binding Supporting Evidence: PMID:15728506 we also demonstrated that TLR10 directly associates with MyD88, the common Toll IL-1 receptor domain adapter. |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | REMOVE | Summary: High-throughput yeast two-hybrid interaction with SPOP. Reason: Uninformative protein binding from a proteome-scale screen; the partner (an E3 ubiquitin ligase substrate adaptor) says nothing about MYD88 molecular function. |
| GO:0005515 protein binding | IPI PMID:16293622 Localization of TLR2 and MyD88 to Chlamydia trachomatis incl... | MODIFY | Summary: TLR2 and MyD88 co-recruit to Chlamydia inclusions; recorded partner TLR2. Reason: Replace protein binding with Toll-like receptor binding, the relevant activity. Proposed replacements: Toll-like receptor binding Supporting Evidence: PMID:16293622 Our data further demonstrate that TLR2 and the adaptor MyD88 are specifically recruited to the bacterial or inclusion membrane during a productive infection with chlamydia |
| GO:0005515 protein binding | IPI PMID:16365431 Modulation of TLR4 signaling by a novel adaptor protein sign... | REMOVE | Summary: STAP-2 binds MyD88 and IKK. Reason: Uninformative protein binding; the adaptor function here belongs to STAP-2. MYD88 adaptor activity is captured by GO:0035591. Supporting Evidence: PMID:16365431 STAP-2, particularly its Src homology 2-like domain, bound to both MyD88 and IkappaB kinase (IKK)-alphabeta |
| GO:0005515 protein binding | IPI PMID:17126326 Extracellular heat shock protein 70 mediates heat stress-ind... | MODIFY | Summary: MyD88 association with TLR2/TLR4 in Hsp70-stimulated A431 cells (partner TLR4; abstract only). Reason: Deferring to the curator, who saw the full text, the interaction is with a TLR; Toll-like receptor binding is informative. Proposed replacements: Toll-like receptor binding Supporting Evidence: PMID:17126326 Both heat stress and pure Hsp70 stimulate activation of TLR2/4 and their association with EGFR. |
| GO:0005515 protein binding | IPI PMID:17126326 Extracellular heat shock protein 70 mediates heat stress-ind... | MODIFY | Summary: Same study, partner TLR2 (abstract only). Reason: As for the TLR4 row: replace with Toll-like receptor binding. Proposed replacements: Toll-like receptor binding Supporting Evidence: PMID:17126326 Both heat stress and pure Hsp70 stimulate activation of TLR2/4 and their association with EGFR. |
| GO:0005515 protein binding | IPI PMID:17258210 MAPPIT analysis of TLR adaptor complexes. | MODIFY | Summary: MAPPIT mapping of TLR-adaptor interactions (partners TLR4, TIRAP, SARM1). Reason: All three partners interact with MyD88 through TIR domains; TIR domain binding is the informative MF. Proposed replacements: TIR domain binding Supporting Evidence: PMID:17258210 We show that the TLR adaptor Mal is critical for linking Myeloid Differentiation primary response protein 88 (MyD88) to TLR2 and TLR4. PMID:17258210 Analysis of the contributions of the different sub-domains of MyD88-adaptor-like protein (Mal) and MyD88 in adaptor homo- and hetero-dimerisation |
| GO:0005515 protein binding | IPI PMID:17258210 MAPPIT analysis of TLR adaptor complexes. | MODIFY | Summary: MAPPIT mapping of TLR-adaptor interactions (partners TLR4, TIRAP, SARM1). Reason: All three partners interact with MyD88 through TIR domains; TIR domain binding is the informative MF. Proposed replacements: TIR domain binding Supporting Evidence: PMID:17258210 We show that the TLR adaptor Mal is critical for linking Myeloid Differentiation primary response protein 88 (MyD88) to TLR2 and TLR4. PMID:17258210 Analysis of the contributions of the different sub-domains of MyD88-adaptor-like protein (Mal) and MyD88 in adaptor homo- and hetero-dimerisation |
| GO:0005515 protein binding | IPI PMID:17258210 MAPPIT analysis of TLR adaptor complexes. | MODIFY | Summary: MAPPIT mapping of TLR-adaptor interactions (partners TLR4, TIRAP, SARM1). Reason: All three partners interact with MyD88 through TIR domains; TIR domain binding is the informative MF. Proposed replacements: TIR domain binding Supporting Evidence: PMID:17258210 We show that the TLR adaptor Mal is critical for linking Myeloid Differentiation primary response protein 88 (MyD88) to TLR2 and TLR4. PMID:17258210 Analysis of the contributions of the different sub-domains of MyD88-adaptor-like protein (Mal) and MyD88 in adaptor homo- and hetero-dimerisation |
| GO:0005515 protein binding | IPI PMID:17567694 Hepatitis C virus nonstructural protein 5A modulates the tol... | REMOVE | Summary: HCV NS5A (and other HCV proteins, IRAK1) interaction with MyD88. Reason: Mostly viral partners: a host-pathogen interaction that describes viral immune evasion, not MYD88 function. The IRAK1 row is captured by the protein kinase binding and signaling adaptor terms. Supporting Evidence: PMID:17567694 Various genotypes of NS5A bound to MyD88, a major adaptor molecule in TLR, inhibited the recruitment of interleukin-1 receptor-associated kinase 1 to MyD88, and impaired cytokine production in response to TLR ligands. |
| GO:0005515 protein binding | IPI PMID:17567694 Hepatitis C virus nonstructural protein 5A modulates the tol... | REMOVE | Summary: HCV NS5A (and other HCV proteins, IRAK1) interaction with MyD88. Reason: Mostly viral partners: a host-pathogen interaction that describes viral immune evasion, not MYD88 function. The IRAK1 row is captured by the protein kinase binding and signaling adaptor terms. Supporting Evidence: PMID:17567694 Various genotypes of NS5A bound to MyD88, a major adaptor molecule in TLR, inhibited the recruitment of interleukin-1 receptor-associated kinase 1 to MyD88, and impaired cytokine production in response to TLR ligands. |
| GO:0005515 protein binding | IPI PMID:17567694 Hepatitis C virus nonstructural protein 5A modulates the tol... | REMOVE | Summary: HCV NS5A (and other HCV proteins, IRAK1) interaction with MyD88. Reason: Mostly viral partners: a host-pathogen interaction that describes viral immune evasion, not MYD88 function. The IRAK1 row is captured by the protein kinase binding and signaling adaptor terms. Supporting Evidence: PMID:17567694 Various genotypes of NS5A bound to MyD88, a major adaptor molecule in TLR, inhibited the recruitment of interleukin-1 receptor-associated kinase 1 to MyD88, and impaired cytokine production in response to TLR ligands. |
| GO:0005515 protein binding | IPI PMID:17567694 Hepatitis C virus nonstructural protein 5A modulates the tol... | REMOVE | Summary: HCV NS5A (and other HCV proteins, IRAK1) interaction with MyD88. Reason: Mostly viral partners: a host-pathogen interaction that describes viral immune evasion, not MYD88 function. The IRAK1 row is captured by the protein kinase binding and signaling adaptor terms. Supporting Evidence: PMID:17567694 Various genotypes of NS5A bound to MyD88, a major adaptor molecule in TLR, inhibited the recruitment of interleukin-1 receptor-associated kinase 1 to MyD88, and impaired cytokine production in response to TLR ligands. |
| GO:0005515 protein binding | IPI PMID:17583698 Distinct roles of TIR and non-TIR regions in the subcellular... | MODIFY | Summary: Subcellular localisation study; partner TIRAP. Reason: TIR-dependent interaction with TIRAP; replace with TIR domain binding. Proposed replacements: TIR domain binding Supporting Evidence: PMID:17583698 The Toll-interleukin I receptor-resistance (TIR) domain does not determine the subcellular localization, but it mediates interaction with specific TLRs. |
| GO:0005515 protein binding | IPI PMID:19948740 AIP1 functions as Arf6-GAP to negatively regulate TLR4 signa... | MODIFY | Summary: AIP1/Arf6 study of TLR4-TIRAP-MyD88 complex; partner TIRAP. Reason: MyD88-TIRAP interaction is TIR-TIR; replace with TIR domain binding. Proposed replacements: TIR domain binding Supporting Evidence: PMID:19948740 which recruits TLR4-MyD88 to phosphatidylinositol 4,5-bisphosphate (PIP(2))-rich sites on the plasma membrane, to activate NF-kappaB and MAPK pathways. |
| GO:0005515 protein binding | IPI PMID:20676093 The transmembrane activator TACI triggers immunoglobulin cla... | MODIFY | Summary: TACI (TNFRSF13B) cytoplasmic motif binds MyD88. Reason: TACI is a TNF-receptor-superfamily receptor lacking a TIR domain; GO:0032813 tumor necrosis factor receptor superfamily binding describes the interaction. Proposed replacements: tumor necrosis factor receptor superfamily binding Supporting Evidence: PMID:20676093 the cytoplasmic domain of TACI encompasses a conserved motif that bound MyD88 |
| GO:0005515 protein binding | IPI PMID:20696886 Aspartate-glutamate-alanine-histidine box motif (DEAH)/RNA h... | REMOVE | Summary: DHX9/DHX36 bind the TIR domain of MyD88 in pDCs. Reason: Here MYD88 is the bound TIR domain, so TIR domain binding would invert the relationship; protein binding is uninformative. The DHX-MyD88 axis is a single-lab finding. Supporting Evidence: PMID:20696886 We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. |
| GO:0005515 protein binding | IPI PMID:20696886 Aspartate-glutamate-alanine-histidine box motif (DEAH)/RNA h... | REMOVE | Summary: Second DHX row (DHX9/DHX36) from the same study. Reason: As above. Supporting Evidence: PMID:20696886 We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. |
| GO:0005515 protein binding | IPI PMID:21334391 The hepatitis B e antigen (HBeAg) targets and suppresses act... | MODIFY | Summary: HBeAg study; partner TIRAP. Reason: MyD88-TIRAP interaction is TIR-TIR; TIR domain binding. Proposed replacements: TIR domain binding Supporting Evidence: PMID:21334391 Co-immunoprecipitation analysis demonstrated HBeAg interacted with TIR proteins Mal and TRAM, while a mutated HBeAg ablated interaction between Mal and MyD88. |
| GO:0005515 protein binding | IPI PMID:21829704 TIRAP, an adaptor protein for TLR2/4, transduces a signal fr... | MODIFY | Summary: RAGE/TIRAP study; partner recorded as TLR4. Reason: Deferring to the curator on the partner, the interaction is with a TLR: Toll-like receptor binding. Proposed replacements: Toll-like receptor binding Supporting Evidence: PMID:21829704 TIRAP and MyD88, which are known to be adaptor proteins for Toll-like receptor-2 and -4 (TLR2/4), bound to the phosphorylated RAGE and transduced a signal to downstream molecules. |
| GO:0005515 protein binding | IPI PMID:21873236 Crystal structure of Toll-like receptor adaptor MAL/TIRAP re... | MODIFY | Summary: MAL/TIRAP crystal structure with co-IP of MyD88-interacting interface. Reason: TIR-TIR interaction: TIR domain binding. Proposed replacements: TIR domain binding Supporting Evidence: PMID:21873236 The structure suggests possible dimerization and MyD88-interacting interfaces, and we confirm the key interface residues by coimmunoprecipitation using site-directed mutants. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: Liver yeast two-hybrid interactome (partners SPOP, TXN, SMAD3, FADD, SIAH1, USP7). Reason: High-throughput protein binding; uninformative for MYD88 molecular function. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: Liver yeast two-hybrid interactome (partners SPOP, TXN, SMAD3, FADD, SIAH1, USP7). Reason: High-throughput protein binding; uninformative for MYD88 molecular function. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: Liver yeast two-hybrid interactome (partners SPOP, TXN, SMAD3, FADD, SIAH1, USP7). Reason: High-throughput protein binding; uninformative for MYD88 molecular function. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: Liver yeast two-hybrid interactome (partners SPOP, TXN, SMAD3, FADD, SIAH1, USP7). Reason: High-throughput protein binding; uninformative for MYD88 molecular function. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: Liver yeast two-hybrid interactome (partners SPOP, TXN, SMAD3, FADD, SIAH1, USP7). Reason: High-throughput protein binding; uninformative for MYD88 molecular function. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: Liver yeast two-hybrid interactome (partners SPOP, TXN, SMAD3, FADD, SIAH1, USP7). Reason: High-throughput protein binding; uninformative for MYD88 molecular function. |
| GO:0005515 protein binding | IPI PMID:22155231 The Brucella TIR-like protein TcpB interacts with the death ... | REMOVE | Summary: Brucella TcpB binds the MyD88 death domain. Reason: Pathogen effector targeting MyD88; a host-pathogen interaction, not a MYD88 function. Supporting Evidence: PMID:22155231 we find that TcpB interacts directly with MyD88 and that this interaction is significantly stronger than the interaction of TcpB with TIRAP |
| GO:0005515 protein binding | IPI PMID:22581261 DOCK8 functions as an adaptor that links TLR-MyD88 signaling... | REMOVE | Summary: DOCK8 associates constitutively with MyD88 in B cells. Reason: Uninformative protein binding; the adaptor function assigned in this paper is DOCK8s. Supporting Evidence: PMID:22581261 DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. |
| GO:0005515 protein binding | IPI PMID:24316379 Functional assessment of the mutational effects of human IRA... | MODIFY | Summary: IRAK4 death-domain variants lose MyD88 binding (gel filtration, NMR). Reason: Direct DD-DD interaction with IRAK4, the Myddosome-forming step: death domain binding. Proposed replacements: death domain binding Supporting Evidence: PMID:24316379 the variant of IRAK4, R12C, as well as R20W, located in the death domain of IRAK4 and regarded as a SNP, caused a loss of interaction with MyD88. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: HuRI binary interaction with IRAK4 (Q69FE3). Reason: The partner is the canonical downstream kinase; protein kinase binding is informative and consistent with focused studies. Proposed replacements: protein kinase binding Supporting Evidence: PMID:24316379 the variant of IRAK4, R12C, as well as R20W, located in the death domain of IRAK4 and regarded as a SNP, caused a loss of interaction with MyD88. |
| GO:0005515 protein binding | IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam... | MODIFY | Summary: Variant-profiling pipeline; interaction with IRAK4. Reason: Protein kinase binding (IRAK4). Proposed replacements: protein kinase binding Supporting Evidence: PMID:24316379 the variant of IRAK4, R12C, as well as R20W, located in the death domain of IRAK4 and regarded as a SNP, caused a loss of interaction with MyD88. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | MODIFY | Summary: Disease-variant interaction perturbation study; interaction with IRAK4. Reason: Protein kinase binding (IRAK4). Proposed replacements: protein kinase binding Supporting Evidence: PMID:24316379 the variant of IRAK4, R12C, as well as R20W, located in the death domain of IRAK4 and regarded as a SNP, caused a loss of interaction with MyD88. |
| GO:0005515 protein binding | IPI PMID:26592460 SARM modulates MyD88-mediated TLR activation through BB-loop... | MODIFY | Summary: Purified SARM1 TIR domain binds MyD88 (BB-loop dependent). Reason: TIR-TIR interaction: TIR domain binding. Proposed replacements: TIR domain binding Supporting Evidence: PMID:26592460 Here we demonstrate that the recombinantly expressed and purified SARM TIR domain interacts with both the major human TLR adaptors, MyD88 and TRIF. |
| GO:0005515 protein binding | IPI PMID:26752465 Increased Expression of Interleukin-36, a Member of the Inte... | MODIFY | Summary: IL-36 assembles MyD88 with IRAK1, TRAF6 and TAK1; partner IRAK1. Reason: Protein kinase binding (IRAK1). Proposed replacements: protein kinase binding Supporting Evidence: PMID:26752465 Stimulation with IL-36Ξ± and IL-36Ξ³ assembled MyD88 adaptor proteins (MyD88, TRAF6, IRAK1, and TAK1) into a complex |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | MODIFY | Summary: Isoform interaction screen; interaction with IRAK4. Reason: Protein kinase binding (IRAK4). Proposed replacements: protein kinase binding Supporting Evidence: PMID:24316379 the variant of IRAK4, R12C, as well as R20W, located in the death domain of IRAK4 and regarded as a SNP, caused a loss of interaction with MyD88. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: BioPlex AP-MS interaction with SPOP. Reason: High-throughput protein binding; uninformative. |
| GO:0005515 protein binding | IPI PMID:29281743 HDAC6 controls innate immune and autophagy responses to TLR-... | REMOVE | Summary: HDAC6 associates with MyD88. Reason: Regulatory partner; protein binding is uninformative about MYD88 activity. Supporting Evidence: PMID:29281743 Moreover, HDAC6 associates with the TLR-adaptor molecule Myeloid differentiation primary response gene 88 (MyD88), and the absence of HDAC6 seems to diminish the NF-ΞΊB induction after TLR stimuli. |
| GO:0005515 protein binding | IPI PMID:29990310 Selective disruption of TLR2-MyD88 interaction inhibits infl... | MODIFY | Summary: TLR2-interacting domain of MyD88 used to make a TLR2-selective peptide. Reason: Toll-like receptor binding. Proposed replacements: Toll-like receptor binding Supporting Evidence: PMID:29990310 we engineered a peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that binds to the BB loop of only TLR2, and not other TLRs. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MODIFY | Summary: Variant interaction profiling; interaction with IRAK4. Reason: Protein kinase binding (IRAK4). Proposed replacements: protein kinase binding Supporting Evidence: PMID:24316379 the variant of IRAK4, R12C, as well as R20W, located in the death domain of IRAK4 and regarded as a SNP, caused a loss of interaction with MyD88. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI reference binary interactome (partners ZNF35, RNF4, SPOPL, NTAQ1, IRAK4). Reason: High-throughput protein binding; the rows cannot be individually tied to partners in this review, and the one informative partner (IRAK4) is captured by protein kinase binding and death domain binding elsewhere. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI reference binary interactome (partners ZNF35, RNF4, SPOPL, NTAQ1, IRAK4). Reason: High-throughput protein binding; the rows cannot be individually tied to partners in this review, and the one informative partner (IRAK4) is captured by protein kinase binding and death domain binding elsewhere. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI reference binary interactome (partners ZNF35, RNF4, SPOPL, NTAQ1, IRAK4). Reason: High-throughput protein binding; the rows cannot be individually tied to partners in this review, and the one informative partner (IRAK4) is captured by protein kinase binding and death domain binding elsewhere. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI reference binary interactome (partners ZNF35, RNF4, SPOPL, NTAQ1, IRAK4). Reason: High-throughput protein binding; the rows cannot be individually tied to partners in this review, and the one informative partner (IRAK4) is captured by protein kinase binding and death domain binding elsewhere. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI reference binary interactome (partners ZNF35, RNF4, SPOPL, NTAQ1, IRAK4). Reason: High-throughput protein binding; the rows cannot be individually tied to partners in this review, and the one informative partner (IRAK4) is captured by protein kinase binding and death domain binding elsewhere. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: BioPlex dual-cell-line AP-MS (partners SPOP, TIRAP). Reason: High-throughput protein binding; the TIRAP interaction is captured by TIR domain binding from focused studies. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Second row from the same BioPlex study. Reason: As above. |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | REMOVE | Summary: Mutation-directed neo-interaction screen (partner SPOP). Reason: High-throughput protein binding; uninformative. |
| GO:0005515 protein binding | IPI PMID:36232715 PAUF Induces Migration of Human Pancreatic Cancer Cells Excl... | MODIFY | Summary: PAUF-induced binding of MyD88 to TLR4 (co-IP) in pancreatic cancer cells. Reason: Toll-like receptor binding. Proposed replacements: Toll-like receptor binding Supporting Evidence: PMID:36232715 We observed binding of MyD88 to TLR4 only 10 min after rPAUF (0.1 ΞΌg/mL) addition (Figure 6A). |
| GO:0005634 nucleus | EXP PMID:21057262 Clinical features and outcome of patients with IRAK-4 and My... | KEEP AS NON CORE | Summary: EXP nucleus annotation citing the clinical report on IRAK-4 and MyD88 deficiency. Reason: The cached full text of this clinical outcome paper contains no subcellular localisation data for MyD88 that could be found; UniProt cites it for the nucleus. The curator may have used a figure not captured in text, so the row is kept, deferring to the curator; nuclear MyD88 is reported only in overexpression systems and has no established function. Supporting Evidence: PMID:21057262 The clinical features of IRAK-4 and MyD88 deficiency were indistinguishable. |
| GO:0005634 nucleus | IDA PMID:22155231 The Brucella TIR-like protein TcpB interacts with the death ... | KEEP AS NON CORE | Summary: Split-GFP imaging of overexpressed MyD88 in cytoplasm and nucleus. Reason: Observed with tagged overexpressed protein; no nuclear function of MYD88 is known. Keep as non-core. Supporting Evidence: PMID:22155231 we detect MyD88 and MyD88TIR in both the cytoplasm and the nucleus. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping (nucleus). Reason: Derived from the UniProt nucleus statement; non-core, as above. Supporting Evidence: PMID:22155231 we detect MyD88 and MyD88TIR in both the cytoplasm and the nucleus. |
| GO:0005737 cytoplasm | EXP PMID:37971847 USP3 plays a critical role in the induction of innate immune... | ACCEPT | Summary: Cytoplasmic MyD88 is the substrate of cytoplasmic USP3. Reason: MYD88 acts in the cytoplasm. Supporting Evidence: PMID:37971847 The cytoplasmic USP3 specifically removes the K63-linked polyubiquitin chains on MyD88, thus negatively regulating TLR/IL1Ξ²-induced inflammatory signaling activation. |
| GO:0005737 cytoplasm | IDA PMID:15361868 Interferon-alpha induction through Toll-like receptors invol... | ACCEPT | Summary: Cytoplasmic MyD88-IRF7-TRAF6 complex (IDA). Reason: MYD88 functions in the cytoplasm; accepted, deferring to the curator on the imaging data (abstract only). Supporting Evidence: PMID:15361868 The death domain of MyD88 interacted with an inhibitory domain of IRF7, and this interaction resulted in activation of the IFN-alpha-dependent promoters. |
| GO:0005737 cytoplasm | IDA PMID:22155231 The Brucella TIR-like protein TcpB interacts with the death ... | ACCEPT | Summary: Split-GFP imaging shows cytoplasmic MyD88. Reason: Correct. Supporting Evidence: PMID:22155231 we detect MyD88 and MyD88TIR in both the cytoplasm and the nucleus. |
| GO:0005737 cytoplasm | IDA PMID:9430229 MyD88: an adapter that recruits IRAK to the IL-1 receptor co... | ACCEPT | Summary: MyD88 recruited from the cytoplasm to the IL-1R complex. Reason: Correct. Supporting Evidence: PMID:9430229 Here we show that MyD88, a previously described protein of unknown function, is recruited to the IL-1 receptor complex following IL-1 stimulation. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping (cytoplasm). Reason: Correct. Supporting Evidence: PMID:37971847 The cytoplasmic USP3 specifically removes the K63-linked polyubiquitin chains on MyD88, thus negatively regulating TLR/IL1Ξ²-induced inflammatory signaling activation. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence: cytosol. Reason: Consistent with MYD88 as a soluble cytosolic adaptor that is recruited to receptors. |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer from mouse: cytosol. Reason: Correct. |
| GO:0005829 cytosol | NAS PMID:36865541 Regulation of innate immune signaling by IRAK proteins. | ACCEPT | Summary: NAS cytosol from the IRAK review. Reason: Correct; the Myddosome assembles on the cytosolic face of receptors. Supporting Evidence: PMID:36865541 The myddosome is a supramolecular signaling complex assembled upon dimerization of IL-1Rs and most TLRs (except TLR3), and is composed of MyD88, IRAK4, IRAK1 and/or IRAK2, in addition to TRAF6. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-166072 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-193665 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-193695 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3134953 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446634 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446648 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446684 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446692 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446694 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446701 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446862 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446868 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446894 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-450133 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5602316 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5602383 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5602606 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-937079 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-975098 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-975175 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-975866 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-975880 | ACCEPT | Summary: Reactome TAS placing MYD88 in the cytosol for a Myddosome or IL-1R reaction. Reason: MYD88 is a cytosolic adaptor; correct. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (PTN000386853): MyD88 active at the plasma membrane. Reason: MYD88 is recruited to the cytoplasmic face of the plasma membrane by activated TLR2/TLR4 (via TIRAP) and IL-1R; the IBA reflects the conserved recruitment and is consistent with human data. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. PMID:19948740 which recruits TLR4-MyD88 to phosphatidylinositol 4,5-bisphosphate (PIP(2))-rich sites on the plasma membrane, to activate NF-kappaB and MAPK pathways. |
| GO:0005886 plasma membrane | IDA PMID:16751103 Phosphoinositide-mediated adaptor recruitment controls Toll-... | ACCEPT | Summary: TIRAP recruits MyD88 to activated TLR4 at the plasma membrane. Reason: Correct; the more precise term GO:0031234 is also carried from this paper. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. PMID:16751103 We find that TIRAP contains a phosphatidylinositol 4,5-bisphosphate (PIP2) binding domain, which mediates TIRAP recruitment to the plasma membrane. |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer from mouse: plasma membrane. Reason: Correct as the site of recruitment by surface TLRs and IL-1R. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166072 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166082 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166091 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166119 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166284 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166286 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166362 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166363 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2262775 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2262777 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602353 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602603 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937022 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937059 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937079 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975852 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975853 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975857 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975861 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975865 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975866 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975873 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975874 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975878 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975879 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975880 | ACCEPT | Summary: Reactome TAS placing MYD88 at the plasma membrane in TLR2/4/5/10 Myddosome reactions. Reason: Correct for plasma-membrane TLRs; MYD88 is peripheral on the cytoplasmic side. |
| GO:0006325 chromatin organization | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Chromatin organization (IEA), transferred from mouse Myd88, from the finding that MyD88-dependent signalling is needed for nucleosome remodelling at secondary-response promoters (PMID:18319258). Reason: The row is transferred from mouse Myd88, annotated from a mutant phenotype in a study showing that MyD88-dependent signalling is required for nucleosome remodelling at secondary-response gene promoters (PMID:18319258), so the claim has an experimental basis. MYD88 is a cytoplasmic signalling adaptor, and the chromatin changes are a downstream consequence of the transcription factor activation it triggers, not something the adaptor does. The term over-reads the phenotype rather than being unsupported, so it is marked as an over-annotation instead of removed. Supporting Evidence: PMID:18319258 This selective dependence correlates with the fact that MyD88 is required for nucleosome remodeling and histone H3K4 trimethylation at secondary response promoters |
| GO:0006338 chromatin remodeling | IEA GO_REF:0000108 | REMOVE | Summary: Inter-ontology inference of chromatin remodeling from the histone chaperone MF. Reason: Inferred from GO:0140674, which is itself unsupported (see that row). MYD88 does not remodel chromatin. Supporting Evidence: PMID:18319258 This selective dependence correlates with the fact that MyD88 is required for nucleosome remodeling and histone H3K4 trimethylation at secondary response promoters |
| GO:0006909 phagocytosis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl transfer (from mouse) of phagocytosis. Reason: MYD88 is not a phagocytic machinery component; effects on uptake are indirect and inconsistent (human macrophage siRNA shows no effect). Supporting Evidence: PMID:30883606 MyD88 silencing did not significantly reduce phagocytosis of either E. coli or S. aureus (Fig 3A and 3B). |
| GO:0006909 phagocytosis | IMP PMID:30883606 The TLR4 adaptor TRAM controls the phagocytosis of Gram-nega... | MARK AS OVER ANNOTATED | Summary: IMP from the TRAM/phagocytosis paper. Reason: The paper reports that MyD88 silencing did not significantly reduce phagocytosis in human macrophages; only mouse Myd88-deficient iBMDMs showed reduced E. coli uptake. The claim is weak and indirect for human MYD88. Supporting Evidence: PMID:30883606 MyD88 silencing did not significantly reduce phagocytosis of either E. coli or S. aureus (Fig 3A and 3B). PMID:30883606 Tlr4-/- mouse macrophages showed impaired uptake of E. coli, however, with less efficiency compared to TRAM- or Myd88-deficient macrophages (S5I Fig). |
| GO:0006915 apoptotic process | IMP PMID:22155231 The Brucella TIR-like protein TcpB interacts with the death ... | KEEP AS NON CORE | Summary: IMP: overexpressed MyD88 death domain shows early signs of apoptosis. Reason: Apoptosis via FADD/caspase-8 is an overexpression-driven side output of MYD88, not a core function. Supporting Evidence: PMID:22155231 In contrast, the isolated DD of MyD88 is more excluded from the nucleus, and its overexpression shows early signs of apoptosis. PMID:10880445 TLR2 signals for apoptosis through MyD88 via a pathway involving Fas-associated death domain protein (FADD) and caspase 8. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: InterPro IEA: signal transduction. Reason: Correct but very general; the specific process is MyD88-dependent TLR signaling. Proposed replacements: MyD88-dependent toll-like receptor signaling pathway Supporting Evidence: PMID:9734363 We now demonstrate that signaling by the human Toll receptor employs an adaptor protein, MyD88, and induces activation of NF-kappaB via the Pelle-like kinase IRAK and the TRAF6 protein, similar to IL-1R-mediated NF-kappaB activation. |
| GO:0007165 signal transduction | NAS PMID:9013863 The cloning and characterization of human MyD88: a member of... | MODIFY | Summary: NAS from the cloning paper: death domain overexpression activates the IL-8 promoter. Reason: Too general; replace with the MyD88-dependent TLR pathway (IL-1 pathway is carried separately). Proposed replacements: MyD88-dependent toll-like receptor signaling pathway Supporting Evidence: PMID:9013863 Overexpression of the death domain region leads to transcriptional activation of the IL-8 promoter. |
| GO:0007166 cell surface receptor signaling pathway | TAS PMID:9374458 IRAK (Pelle) family member IRAK-2 and MyD88 as proximal medi... | MODIFY | Summary: TAS cell surface receptor signaling pathway (IL-1R signaling complex). Reason: The cited work is about IL-1R signaling; replace with interleukin-1-mediated signaling pathway. Proposed replacements: interleukin-1-mediated signaling pathway Supporting Evidence: PMID:9374458 Both associate with the IL-1R signaling complex. |
| GO:0007249 canonical NF-kappaB signal transduction | NAS PMID:38605168 OTUD5 promotes the inflammatory immune response by enhancing... | KEEP AS NON CORE | Summary: NAS: MyD88 oligomerization leads to NF-kappaB activation. Reason: NF-kappaB activation is the main downstream output, but the canonical NF-kappaB cascade proper (IKK activation, IkB degradation) is carried out by TRAF6/TAK1/IKK downstream of MYD88. Supporting Evidence: PMID:38605168 This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-ΞΊB and MAPK signaling and production of inflammatory cytokines. |
| GO:0007254 JNK cascade | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer (rat): JNK cascade. Reason: JNK activation is a downstream output of MyD88-dependent signalling, not a step MYD88 performs. Supporting Evidence: PMID:38605168 This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-ΞΊB and MAPK signaling and production of inflammatory cytokines. |
| GO:0008063 Toll signaling pathway | IBA GO_REF:0000033 | MODIFY | Summary: IBA (PTN000386853, donors fly Myd88 and rat Myd88): Toll signaling pathway. Reason: GO:0008063 is defined for ligand binding to "the receptor Toll" and is not an ancestor of GO:0002224 toll-like receptor signaling pathway (checked in OLS). The IBD at the MyD88 node correctly captures an ancestral adaptor role in Toll-family receptor signaling, but human MYD88 functions downstream of vertebrate TLRs and IL-1R family receptors, not Toll. The vertebrate-appropriate term is GO:0002755. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: LINEAGE OR TAXON MISMATCH GRANULARITY MISMATCH Sources checked: PANTHER:PTN000386853 Β· PTN000386853 SUPPORTS SOURCE BUT NOT TARGET The MyD88-family node carries both GO:0008063 (seeded from fly Myd88 and rat Myd88) and the vertebrate TLR terms. The ancestral adaptor role in Toll-family receptor signalling is sound, but GO:0008063 names the Drosophila Toll receptor pathway and is not an ancestor of GO:0002224, so for vertebrate descendants the TLR pathway term is the correct scope. Proposed replacements: MyD88-dependent toll-like receptor signaling pathway Supporting Evidence: PMID:9734363 We now demonstrate that signaling by the human Toll receptor employs an adaptor protein, MyD88, and induces activation of NF-kappaB via the Pelle-like kinase IRAK and the TRAF6 protein, similar to IL-1R-mediated NF-kappaB activation. PMID:36865541 Signaling via most TLRs and IL-1Rs is mediated by the protein myeloid differentiation primary-response protein 88 (MyD88). |
| GO:0008063 Toll signaling pathway | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl transfer (rat) of Toll signaling pathway. Reason: As for the IBA row: GO:0008063 is the Drosophila Toll pathway; for human MYD88 use the MyD88-dependent TLR pathway. Proposed replacements: MyD88-dependent toll-like receptor signaling pathway Supporting Evidence: PMID:9734363 We now demonstrate that signaling by the human Toll receptor employs an adaptor protein, MyD88, and induces activation of NF-kappaB via the Pelle-like kinase IRAK and the TRAF6 protein, similar to IL-1R-mediated NF-kappaB activation. |
| GO:0009617 response to bacterium | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA: response to bacterium. Reason: True at organism level (MyD88 deficiency causes pyogenic bacterial infections) but downstream of the core signalling role. Supporting Evidence: PMID:21057262 The clinical features of IRAK-4 and MyD88 deficiency were indistinguishable. |
| GO:0009986 cell surface | IDA PMID:22851693 Ξ²-TrCP-mediated IRAK1 degradation releases TAK1-TRAF6 from t... | MODIFY | Summary: IDA cell surface in the IL-1 complex I membrane-translocation study. Reason: MYD88 has no extracellular part; the study examines membrane-bound receptor complexes on the cytoplasmic side. Replace with extrinsic component of cytoplasmic side of plasma membrane. Proposed replacements: extrinsic component of cytoplasmic side of plasma membrane Supporting Evidence: PMID:22851693 It is important to note that the modified IRAK1 is always membrane associated and detected in membrane-bound receptor complex I and II |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975098 | ACCEPT | Summary: Reactome TAS: MYD88 at the endosome membrane in TLR7/8/9 reactions. Reason: MYD88 is recruited to endosomal TLR7, TLR8 and TLR9; correct (peripheral on the cytoplasmic face). Supporting Evidence: PMID:40980882 Phosphorylated TLR9 is critical for interaction with its adaptor protein, MyD88, and activating downstream signaling. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975100 | ACCEPT | Summary: Reactome TAS: MYD88 at the endosome membrane in TLR7/8/9 reactions. Reason: MYD88 is recruited to endosomal TLR7, TLR8 and TLR9; correct (peripheral on the cytoplasmic face). Supporting Evidence: PMID:40980882 Phosphorylated TLR9 is critical for interaction with its adaptor protein, MyD88, and activating downstream signaling. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975106 | ACCEPT | Summary: Reactome TAS: MYD88 at the endosome membrane in TLR7/8/9 reactions. Reason: MYD88 is recruited to endosomal TLR7, TLR8 and TLR9; correct (peripheral on the cytoplasmic face). Supporting Evidence: PMID:40980882 Phosphorylated TLR9 is critical for interaction with its adaptor protein, MyD88, and activating downstream signaling. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975111 | ACCEPT | Summary: Reactome TAS: MYD88 at the endosome membrane in TLR7/8/9 reactions. Reason: MYD88 is recruited to endosomal TLR7, TLR8 and TLR9; correct (peripheral on the cytoplasmic face). Supporting Evidence: PMID:40980882 Phosphorylated TLR9 is critical for interaction with its adaptor protein, MyD88, and activating downstream signaling. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975115 | ACCEPT | Summary: Reactome TAS: MYD88 at the endosome membrane in TLR7/8/9 reactions. Reason: MYD88 is recruited to endosomal TLR7, TLR8 and TLR9; correct (peripheral on the cytoplasmic face). Supporting Evidence: PMID:40980882 Phosphorylated TLR9 is critical for interaction with its adaptor protein, MyD88, and activating downstream signaling. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975118 | ACCEPT | Summary: Reactome TAS: MYD88 at the endosome membrane in TLR7/8/9 reactions. Reason: MYD88 is recruited to endosomal TLR7, TLR8 and TLR9; correct (peripheral on the cytoplasmic face). Supporting Evidence: PMID:40980882 Phosphorylated TLR9 is critical for interaction with its adaptor protein, MyD88, and activating downstream signaling. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975125 | ACCEPT | Summary: Reactome TAS: MYD88 at the endosome membrane in TLR7/8/9 reactions. Reason: MYD88 is recruited to endosomal TLR7, TLR8 and TLR9; correct (peripheral on the cytoplasmic face). Supporting Evidence: PMID:40980882 Phosphorylated TLR9 is critical for interaction with its adaptor protein, MyD88, and activating downstream signaling. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975134 | ACCEPT | Summary: Reactome TAS: MYD88 at the endosome membrane in TLR7/8/9 reactions. Reason: MYD88 is recruited to endosomal TLR7, TLR8 and TLR9; correct (peripheral on the cytoplasmic face). Supporting Evidence: PMID:40980882 Phosphorylated TLR9 is critical for interaction with its adaptor protein, MyD88, and activating downstream signaling. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975156 | ACCEPT | Summary: Reactome TAS: MYD88 at the endosome membrane in TLR7/8/9 reactions. Reason: MYD88 is recruited to endosomal TLR7, TLR8 and TLR9; correct (peripheral on the cytoplasmic face). Supporting Evidence: PMID:40980882 Phosphorylated TLR9 is critical for interaction with its adaptor protein, MyD88, and activating downstream signaling. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975160 | ACCEPT | Summary: Reactome TAS: MYD88 at the endosome membrane in TLR7/8/9 reactions. Reason: MYD88 is recruited to endosomal TLR7, TLR8 and TLR9; correct (peripheral on the cytoplasmic face). Supporting Evidence: PMID:40980882 Phosphorylated TLR9 is critical for interaction with its adaptor protein, MyD88, and activating downstream signaling. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975170 | ACCEPT | Summary: Reactome TAS: MYD88 at the endosome membrane in TLR7/8/9 reactions. Reason: MYD88 is recruited to endosomal TLR7, TLR8 and TLR9; correct (peripheral on the cytoplasmic face). Supporting Evidence: PMID:40980882 Phosphorylated TLR9 is critical for interaction with its adaptor protein, MyD88, and activating downstream signaling. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975175 | ACCEPT | Summary: Reactome TAS: MYD88 at the endosome membrane in TLR7/8/9 reactions. Reason: MYD88 is recruited to endosomal TLR7, TLR8 and TLR9; correct (peripheral on the cytoplasmic face). Supporting Evidence: PMID:40980882 Phosphorylated TLR9 is critical for interaction with its adaptor protein, MyD88, and activating downstream signaling. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975180 | ACCEPT | Summary: Reactome TAS: MYD88 at the endosome membrane in TLR7/8/9 reactions. Reason: MYD88 is recruited to endosomal TLR7, TLR8 and TLR9; correct (peripheral on the cytoplasmic face). Supporting Evidence: PMID:40980882 Phosphorylated TLR9 is critical for interaction with its adaptor protein, MyD88, and activating downstream signaling. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975188 | ACCEPT | Summary: Reactome TAS: MYD88 at the endosome membrane in TLR7/8/9 reactions. Reason: MYD88 is recruited to endosomal TLR7, TLR8 and TLR9; correct (peripheral on the cytoplasmic face). Supporting Evidence: PMID:40980882 Phosphorylated TLR9 is critical for interaction with its adaptor protein, MyD88, and activating downstream signaling. |
| GO:0010467 gene expression | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl transfer (mouse): gene expression. Reason: Uninformative high-level process; MYD88 regulates gene expression only through signalling. |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer (mouse): positive regulation of gene expression. Reason: Indirect output of MyD88 signalling. Supporting Evidence: PMID:33718825 Thus the TLR8/MYD88 pathway is required for viral GU-rich RNA-induced IL-1Ξ², TNF, and IL-6 expression from human macrophages |
| GO:0010628 positive regulation of gene expression | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: positive regulation of gene expression. Reason: Indirect output of MyD88 signalling. Supporting Evidence: PMID:33718825 Thus the TLR8/MYD88 pathway is required for viral GU-rich RNA-induced IL-1Ξ², TNF, and IL-6 expression from human macrophages |
| GO:0014075 response to amine | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl transfer (rat): response to amine. Reason: Rat expression/physiology annotation with no mechanistic link to MYD88 function. |
| GO:0019221 cytokine-mediated signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer (rat): cytokine-mediated signaling pathway. Reason: Correct: MYD88 is the adaptor for IL-1, IL-18, IL-33 and IL-36 receptor signalling. Supporting Evidence: PMID:36865541 Responses to these cytokines are mediated by the IL-1 receptor (IL-1R) and the closely related IL-18R and IL-33R, all of which employs MyD88 as signaling adaptor, similarly to TLRs |
| GO:0019897 extrinsic component of plasma membrane | IDA PMID:9430229 MyD88: an adapter that recruits IRAK to the IL-1 receptor co... | MODIFY | Summary: IDA: MyD88 recruited to the IL-1 receptor complex. Reason: Correct but the more precise term is extrinsic component of cytoplasmic side of plasma membrane. Proposed replacements: extrinsic component of cytoplasmic side of plasma membrane Supporting Evidence: PMID:9430229 Here we show that MyD88, a previously described protein of unknown function, is recruited to the IL-1 receptor complex following IL-1 stimulation. |
| GO:0031234 extrinsic component of cytoplasmic side of plasma membrane | IDA PMID:16751103 Phosphoinositide-mediated adaptor recruitment controls Toll-... | ACCEPT | Summary: IDA: TIRAP delivers MyD88 to activated TLR4 at the plasma membrane. Reason: Precise and correct location of the active adaptor. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. PMID:16751103 We find that TIRAP contains a phosphatidylinositol 4,5-bisphosphate (PIP2) binding domain, which mediates TIRAP recruitment to the plasma membrane. |
| GO:0031663 lipopolysaccharide-mediated signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer (rat): lipopolysaccharide-mediated signaling pathway. Reason: MYD88 is the adaptor of the TLR4 MyD88 arm. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. |
| GO:0032481 positive regulation of type I interferon production | IMP PMID:23633945 HCV-induced miR-21 contributes to evasion of host immune sys... | KEEP AS NON CORE | Summary: IMP: miR-21 targeting of MyD88 reduces HCV-induced type I IFN. Reason: Type I IFN production is a downstream output of TLR7/8/9-MyD88-IRF7 signaling. Supporting Evidence: PMID:23633945 Furthermore, we demonstrated that miR-21 targets two important factors in the TLR signaling pathway, myeloid differentiation factor 88 (MyD88) and interleukin-1 receptor-associated kinase 1 (IRAK1), which are involved in HCV-induced type I IFN production. PMID:15361868 The death domain of MyD88 interacted with an inhibitory domain of IRF7, and this interaction resulted in activation of the IFN-alpha-dependent promoters. |
| GO:0032731 positive regulation of interleukin-1 beta production | IDA PMID:33718825 SARS-CoV-2, SARS-CoV-1, and HIV-1 derived ssRNA sequences ac... | KEEP AS NON CORE | Summary: IDA: TLR8/MyD88 required for IL-1beta production to viral GU-rich RNA. Reason: Cytokine output of MyD88 signalling. Supporting Evidence: PMID:33718825 Thus the TLR8/MYD88 pathway is required for viral GU-rich RNA-induced IL-1Ξ², TNF, and IL-6 expression from human macrophages |
| GO:0032740 positive regulation of interleukin-17 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse-sourced (IEA/ISS) positive regulation of cytokine production (IL-17, IL-23 or IL-6). Reason: Cytokine output downstream of MyD88 signalling; non-core. Supporting Evidence: PMID:33718825 Thus the TLR8/MYD88 pathway is required for viral GU-rich RNA-induced IL-1Ξ², TNF, and IL-6 expression from human macrophages |
| GO:0032740 positive regulation of interleukin-17 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse-sourced (IEA/ISS) positive regulation of cytokine production (IL-17, IL-23 or IL-6). Reason: Cytokine output downstream of MyD88 signalling; non-core. Supporting Evidence: PMID:33718825 Thus the TLR8/MYD88 pathway is required for viral GU-rich RNA-induced IL-1Ξ², TNF, and IL-6 expression from human macrophages |
| GO:0032747 positive regulation of interleukin-23 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse-sourced (IEA/ISS) positive regulation of cytokine production (IL-17, IL-23 or IL-6). Reason: Cytokine output downstream of MyD88 signalling; non-core. Supporting Evidence: PMID:33718825 Thus the TLR8/MYD88 pathway is required for viral GU-rich RNA-induced IL-1Ξ², TNF, and IL-6 expression from human macrophages |
| GO:0032747 positive regulation of interleukin-23 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse-sourced (IEA/ISS) positive regulation of cytokine production (IL-17, IL-23 or IL-6). Reason: Cytokine output downstream of MyD88 signalling; non-core. Supporting Evidence: PMID:33718825 Thus the TLR8/MYD88 pathway is required for viral GU-rich RNA-induced IL-1Ξ², TNF, and IL-6 expression from human macrophages |
| GO:0032755 positive regulation of interleukin-6 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse-sourced (IEA/ISS) positive regulation of cytokine production (IL-17, IL-23 or IL-6). Reason: Cytokine output downstream of MyD88 signalling; non-core. Supporting Evidence: PMID:33718825 Thus the TLR8/MYD88 pathway is required for viral GU-rich RNA-induced IL-1Ξ², TNF, and IL-6 expression from human macrophages |
| GO:0032755 positive regulation of interleukin-6 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse-sourced (IEA/ISS) positive regulation of cytokine production (IL-17, IL-23 or IL-6). Reason: Cytokine output downstream of MyD88 signalling; non-core. Supporting Evidence: PMID:33718825 Thus the TLR8/MYD88 pathway is required for viral GU-rich RNA-induced IL-1Ξ², TNF, and IL-6 expression from human macrophages |
| GO:0032757 positive regulation of interleukin-8 production | IMP PMID:20219467 Identification of MyD88 as a novel target of miR-155, involv... | KEEP AS NON CORE | Summary: IMP: miR-155 lowers MyD88 and IL-8 in H. pylori infection. Reason: IL-8 production is a downstream output. Supporting Evidence: PMID:20219467 Furthermore, the overexpression of miR-155 led to significantly reduced IL-8 production induced by H. pylori infection. |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer (rat): protein-containing complex. Reason: MYD88 is a subunit of the Myddosome; GO has no Myddosome complex term, so this general term is not wrong but uninformative. Supporting Evidence: PMID:36865541 The myddosome is a supramolecular signaling complex assembled upon dimerization of IL-1Rs and most TLRs (except TLR3), and is composed of MyD88, IRAK4, IRAK1 and/or IRAK2, in addition to TRAF6. |
| GO:0034142 toll-like receptor 4 signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: toll-like receptor 4 signaling pathway. Reason: MYD88 is the adaptor of the MyD88 arm of TLR4 signaling; the human gene is among the IBD donors. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. |
| GO:0034142 toll-like receptor 4 signaling pathway | IDA PMID:16751103 Phosphoinositide-mediated adaptor recruitment controls Toll-... | ACCEPT | Summary: IDA: MyD88 delivery to TLR4 via TIRAP. Reason: Core. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. |
| GO:0034146 toll-like receptor 5 signaling pathway | IDA PMID:16751103 Phosphoinositide-mediated adaptor recruitment controls Toll-... | ACCEPT | Summary: IDA: TLR5 signaling (abstract only cached). Reason: TLR5 signals exclusively through MYD88; deferring to the curator on the specific data. Supporting Evidence: PMID:36865541 Signaling via most TLRs and IL-1Rs is mediated by the protein myeloid differentiation primary-response protein 88 (MyD88). |
| GO:0034158 toll-like receptor 8 signaling pathway | IDA PMID:33718825 SARS-CoV-2, SARS-CoV-1, and HIV-1 derived ssRNA sequences ac... | ACCEPT | Summary: IDA: TLR8/MYD88 pathway in human macrophages. Reason: Core. Supporting Evidence: PMID:33718825 Thus the TLR8/MYD88 pathway is required for viral GU-rich RNA-induced IL-1Ξ², TNF, and IL-6 expression from human macrophages |
| GO:0034162 toll-like receptor 9 signaling pathway | IDA PMID:40980882 TLR9 signaling requires ligand-induced phosphorylation of tw... | ACCEPT | Summary: IDA: TLR9 phosphorylation required for MyD88 recruitment. Reason: Core. Supporting Evidence: PMID:40980882 Phosphorylated TLR9 is critical for interaction with its adaptor protein, MyD88, and activating downstream signaling. |
| GO:0035325 Toll-like receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: Toll-like receptor binding. Reason: MYD88 binds TLR TIR domains; consistent with human experimental data. Supporting Evidence: PMID:17258210 We show that the TLR adaptor Mal is critical for linking Myeloid Differentiation primary response protein 88 (MyD88) to TLR2 and TLR4. PMID:29990310 we engineered a peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that binds to the BB loop of only TLR2, and not other TLRs. |
| GO:0035325 Toll-like receptor binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer (mouse): Toll-like receptor binding. Reason: Correct. Supporting Evidence: PMID:29990310 we engineered a peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that binds to the BB loop of only TLR2, and not other TLRs. |
| GO:0035591 signaling adaptor activity | IDA PMID:16751103 Phosphoinositide-mediated adaptor recruitment controls Toll-... | ACCEPT | Summary: IDA: signaling adaptor activity at TLR4. Reason: Core MF: MYD88 bridges activated TLR/IL-1R TIR domains to IRAK4 and assembles the Myddosome. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. PMID:38961291 within most myddosomes, MyD88 forms barrel-like structures that function as scaffolds for effector protein recruitment. |
| GO:0035591 signaling adaptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer (mouse): signaling adaptor activity. Reason: Core MF. Supporting Evidence: PMID:9430229 MyD88 binds to both IRAK (IL-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of IRAK with the receptor. |
| GO:0038124 toll-like receptor TLR6:TLR2 signaling pathway | IDA PMID:36964784 BacSp222 bacteriocin as a novel ligand for TLR2/TLR6 heterod... | ACCEPT | Summary: IDA: TLR2/TLR6 signalling to BacSp222 is MyD88 dependent. Reason: Correct for the TLR2 heterodimer pathway. Supporting Evidence: PMID:36964784 Summarizing, our studies revealed the TLR2/TLR6/MyD88/NF-ΞΊB pathway as a potential mechanism explaining the inflammatory response activated by BacSp222 bacteriocin in human and murine cells. |
| GO:0038172 interleukin-33-mediated signaling pathway | IDA PMID:18802081 IL-33 induces antigen-specific IL-5+ T cells and promotes al... | ACCEPT | Summary: IDA: IL-33-induced T cell polarisation requires MyD88 (human and mouse cells). Reason: MYD88 is the adaptor for ST2/IL1RL1; correct. Supporting Evidence: PMID:18802081 This polarization requires IL-1R-related molecule and MyD88 but not IL-4 or STAT6. PMID:36865541 Responses to these cytokines are mediated by the IL-1 receptor (IL-1R) and the closely related IL-18R and IL-33R, all of which employs MyD88 as signaling adaptor, similarly to TLRs |
| GO:0042742 defense response to bacterium | IMP PMID:20219467 Identification of MyD88 as a novel target of miR-155, involv... | KEEP AS NON CORE | Summary: IMP: miR-155 lowers MyD88 and H. pylori-induced IL-8. Reason: Organism-level defence is a consequence of MyD88 signalling; the evidence (IL-8 readout) is indirect. Supporting Evidence: PMID:20219467 Furthermore, the overexpression of miR-155 led to significantly reduced IL-8 production induced by H. pylori infection. |
| GO:0042802 identical protein binding | IPI PMID:11544529 Mal (MyD88-adapter-like) is required for Toll-like receptor-... | ACCEPT | Summary: MYD88 self-interaction (homodimer/oligomer). Reason: MYD88 homo-oligomerises through its death and TIR domains; DD oligomerisation builds the Myddosome helix. Identical protein binding is informative here. Supporting Evidence: PMID:11544529 Mal can form homodimers and can also form heterodimers with MyD88. PMID:38605168 This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-ΞΊB and MAPK signaling and production of inflammatory cytokines. |
| GO:0042802 identical protein binding | IPI PMID:17258210 MAPPIT analysis of TLR adaptor complexes. | ACCEPT | Summary: MYD88 self-interaction (homodimer/oligomer). Reason: MYD88 homo-oligomerises through its death and TIR domains; DD oligomerisation builds the Myddosome helix. Identical protein binding is informative here. Supporting Evidence: PMID:17258210 Analysis of the contributions of the different sub-domains of MyD88-adaptor-like protein (Mal) and MyD88 in adaptor homo- and hetero-dimerisation PMID:38605168 This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-ΞΊB and MAPK signaling and production of inflammatory cytokines. |
| GO:0042802 identical protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | ACCEPT | Summary: MYD88 self-interaction (homodimer/oligomer). Reason: MYD88 homo-oligomerises through its death and TIR domains; DD oligomerisation builds the Myddosome helix. Identical protein binding is informative here. This row comes from a high-throughput screen that re-detects the known self-interaction. Supporting Evidence: PMID:22155231 TcpB disrupts MyD88(DD)-MyD88(DD), MyD88(DD)-MyD88(TIR) and MyD88(DD)-MyD88 interactions but not MyD88-MyD88 or MyD88(TIR)-MyD88(TIR) interactions. PMID:38605168 This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-ΞΊB and MAPK signaling and production of inflammatory cytokines. |
| GO:0042802 identical protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | ACCEPT | Summary: MYD88 self-interaction (homodimer/oligomer). Reason: MYD88 homo-oligomerises through its death and TIR domains; DD oligomerisation builds the Myddosome helix. Identical protein binding is informative here. This row comes from a high-throughput screen that re-detects the known self-interaction. Supporting Evidence: PMID:22155231 TcpB disrupts MyD88(DD)-MyD88(DD), MyD88(DD)-MyD88(TIR) and MyD88(DD)-MyD88 interactions but not MyD88-MyD88 or MyD88(TIR)-MyD88(TIR) interactions. PMID:38605168 This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-ΞΊB and MAPK signaling and production of inflammatory cytokines. |
| GO:0042802 identical protein binding | IPI PMID:22155231 The Brucella TIR-like protein TcpB interacts with the death ... | ACCEPT | Summary: MYD88 self-interaction (homodimer/oligomer). Reason: MYD88 homo-oligomerises through its death and TIR domains; DD oligomerisation builds the Myddosome helix. Identical protein binding is informative here. Supporting Evidence: PMID:22155231 TcpB disrupts MyD88(DD)-MyD88(DD), MyD88(DD)-MyD88(TIR) and MyD88(DD)-MyD88 interactions but not MyD88-MyD88 or MyD88(TIR)-MyD88(TIR) interactions. PMID:38605168 This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-ΞΊB and MAPK signaling and production of inflammatory cytokines. |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | ACCEPT | Summary: MYD88 self-interaction (homodimer/oligomer). Reason: MYD88 homo-oligomerises through its death and TIR domains; DD oligomerisation builds the Myddosome helix. Identical protein binding is informative here. This row comes from a high-throughput screen that re-detects the known self-interaction. Supporting Evidence: PMID:22155231 TcpB disrupts MyD88(DD)-MyD88(DD), MyD88(DD)-MyD88(TIR) and MyD88(DD)-MyD88 interactions but not MyD88-MyD88 or MyD88(TIR)-MyD88(TIR) interactions. PMID:38605168 This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-ΞΊB and MAPK signaling and production of inflammatory cytokines. |
| GO:0042802 identical protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | ACCEPT | Summary: MYD88 self-interaction (homodimer/oligomer). Reason: MYD88 homo-oligomerises through its death and TIR domains; DD oligomerisation builds the Myddosome helix. Identical protein binding is informative here. This row comes from a high-throughput screen that re-detects the known self-interaction. Supporting Evidence: PMID:22155231 TcpB disrupts MyD88(DD)-MyD88(DD), MyD88(DD)-MyD88(TIR) and MyD88(DD)-MyD88 interactions but not MyD88-MyD88 or MyD88(TIR)-MyD88(TIR) interactions. PMID:38605168 This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-ΞΊB and MAPK signaling and production of inflammatory cytokines. |
| GO:0042802 identical protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | ACCEPT | Summary: MYD88 self-interaction (homodimer/oligomer). Reason: MYD88 homo-oligomerises through its death and TIR domains; DD oligomerisation builds the Myddosome helix. Identical protein binding is informative here. This row comes from a high-throughput screen that re-detects the known self-interaction. Supporting Evidence: PMID:22155231 TcpB disrupts MyD88(DD)-MyD88(DD), MyD88(DD)-MyD88(TIR) and MyD88(DD)-MyD88 interactions but not MyD88-MyD88 or MyD88(TIR)-MyD88(TIR) interactions. PMID:38605168 This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-ΞΊB and MAPK signaling and production of inflammatory cytokines. |
| GO:0042802 identical protein binding | IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m... | ACCEPT | Summary: MYD88 self-interaction (homodimer/oligomer). Reason: MYD88 homo-oligomerises through its death and TIR domains; DD oligomerisation builds the Myddosome helix. Identical protein binding is informative here. This row comes from a high-throughput screen that re-detects the known self-interaction. Supporting Evidence: PMID:22155231 TcpB disrupts MyD88(DD)-MyD88(DD), MyD88(DD)-MyD88(TIR) and MyD88(DD)-MyD88 interactions but not MyD88-MyD88 or MyD88(TIR)-MyD88(TIR) interactions. PMID:38605168 This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-ΞΊB and MAPK signaling and production of inflammatory cytokines. |
| GO:0042802 identical protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | ACCEPT | Summary: MYD88 self-interaction (homodimer/oligomer). Reason: MYD88 homo-oligomerises through its death and TIR domains; DD oligomerisation builds the Myddosome helix. Identical protein binding is informative here. This row comes from a high-throughput screen that re-detects the known self-interaction. Supporting Evidence: PMID:22155231 TcpB disrupts MyD88(DD)-MyD88(DD), MyD88(DD)-MyD88(TIR) and MyD88(DD)-MyD88 interactions but not MyD88-MyD88 or MyD88(TIR)-MyD88(TIR) interactions. PMID:38605168 This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-ΞΊB and MAPK signaling and production of inflammatory cytokines. |
| GO:0042832 defense response to protozoan | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: defense response to protozoan. Reason: Mouse Myd88-deficient animals are susceptible to protozoa (Toxoplasma); organism-level, downstream of TLR11/12-MyD88 signalling which is mouse-specific in part. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro IEA: positive regulation of canonical NF-kappaB signal transduction. Reason: MYD88 positively regulates NF-kappaB activation by recruiting IRAKs; accepted. Supporting Evidence: PMID:9734363 We now demonstrate that signaling by the human Toll receptor employs an adaptor protein, MyD88, and induces activation of NF-kappaB via the Pelle-like kinase IRAK and the TRAF6 protein, similar to IL-1R-mediated NF-kappaB activation. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IEP PMID:12761501 Large-scale identification and characterization of human gen... | ACCEPT | Summary: IEP from an overexpression screen for NF-kappaB activators. Reason: MYD88 overexpression activates NF-kappaB reporters; consistent with its known role. Supporting Evidence: PMID:12761501 For analysis of the NF-kappaB signaling pathway, we introduced each of the cDNAs into human embryonic kidney 293 cells and examined whether it activated the transcription of a luciferase reporter gene driven by a promoter containing the consensus NF-kappaB binding sites. PMID:9013863 Overexpression of the death domain region leads to transcriptional activation of the IL-8 promoter. |
| GO:0043200 response to amino acid | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl transfer (rat): response to amino acid. Reason: Rat physiology annotation with no mechanistic basis for MYD88. |
| GO:0043405 regulation of MAP kinase activity | NAS PMID:38605168 OTUD5 promotes the inflammatory immune response by enhancing... | KEEP AS NON CORE | Summary: NAS: MyD88 oligomerization promotes MAPK signalling. Reason: Downstream output. Supporting Evidence: PMID:38605168 This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-ΞΊB and MAPK signaling and production of inflammatory cytokines. |
| GO:0043588 skin development | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl transfer (mouse): skin development. Reason: The mouse source (PMID:31164412) is a skin-carcinogenesis study; it does not show a role for Myd88 in skin development. Supporting Evidence: PMID:31164412 By deleting Myd88 in keratinocytes or specific bone marrow subpopulations in oncogenic RAS-mediated skin carcinogenesis |
| GO:0044546 NLRP3 inflammasome complex assembly | NAS PMID:36865541 Regulation of innate immune signaling by IRAK proteins. | MODIFY | Summary: NAS (IRAK review): NLRP3 inflammasome complex assembly. Reason: MYD88 is not part of the NLRP3 inflammasome; TLR-MyD88 signalling primes and licenses assembly. Replace with positive regulation of NLRP3 inflammasome complex assembly. Proposed replacements: positive regulation of NLRP3 inflammasome complex assembly Supporting Evidence: PMID:33718825 With the use of inhibitors and RNAi, we also demonstrate that activation of the NLRP3 inflammasome by GU-rich RNA is specifically TLR8-dependent and RNA-mediated, leading to CASP1 activation and the conversion of pro-IL-1Ξ² to its active form. |
| GO:0045087 innate immune response | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: innate immune response. Reason: Correct and conserved across the MyD88 family. Supporting Evidence: PMID:9734363 our findings implicate MyD88 as a general adaptor/regulator molecule for the Toll/IL-1R family of receptors for innate immunity. |
| GO:0045471 response to ethanol | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl transfer (rat): response to ethanol. Reason: Rat physiology annotation with no mechanistic basis for MYD88. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl transfer (mouse): positive regulation of transcription by RNA polymerase II. Reason: MYD88 is not a transcription regulator; transcriptional effects are indirect via NF-kappaB/IRFs. |
| GO:0048661 positive regulation of smooth muscle cell proliferation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Positive regulation of smooth muscle cell proliferation (IEA), transferred from rat Myd88, from a study of IL-18-induced CXCL16 expression in aortic smooth muscle cells (PMID:15890643). Reason: The row is transferred from rat Myd88, annotated from a mutant phenotype in a study of interleukin-18 signalling in aortic smooth muscle cells, where IL-18 induces the chemokine CXCL16, which promotes smooth muscle cell proliferation, through MyD88, IRAK and TRAF6 (PMID:15890643). The claim therefore has an experimental basis. MYD88 acts here as the receptor-proximal adaptor, and proliferation is a consequence of the cytokine response in one cell type rather than a process in which MYD88 itself takes part. The term over-reads the pathway output and is marked as an over-annotation, as for IRAK4 in the same pathway, rather than removed. |
| GO:0050727 regulation of inflammatory response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer (mouse): regulation of inflammatory response. Reason: Downstream output of MyD88 signalling. Supporting Evidence: PMID:37971847 The cytoplasmic USP3 specifically removes the K63-linked polyubiquitin chains on MyD88, thus negatively regulating TLR/IL1Ξ²-induced inflammatory signaling activation. |
| GO:0050727 regulation of inflammatory response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: regulation of inflammatory response. Reason: Downstream output. Supporting Evidence: PMID:37971847 The cytoplasmic USP3 specifically removes the K63-linked polyubiquitin chains on MyD88, thus negatively regulating TLR/IL1Ξ²-induced inflammatory signaling activation. |
| GO:0050830 defense response to Gram-positive bacterium | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA: defense response to Gram-positive bacterium. Reason: Organism-level role conserved from fly Myd88 to mammals; human MyD88 deficiency causes pyogenic bacterial infection. Non-core relative to the signalling function. Supporting Evidence: PMID:21057262 The clinical features of IRAK-4 and MyD88 deficiency were indistinguishable. |
| GO:0050830 defense response to Gram-positive bacterium | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer (mouse): defense response to Gram-positive bacterium. Reason: As above. Supporting Evidence: PMID:21057262 The clinical features of IRAK-4 and MyD88 deficiency were indistinguishable. |
| GO:0050830 defense response to Gram-positive bacterium | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: defense response to Gram-positive bacterium. Reason: As above. Supporting Evidence: PMID:21057262 The clinical features of IRAK-4 and MyD88 deficiency were indistinguishable. |
| GO:0051607 defense response to virus | IDA PMID:33718825 SARS-CoV-2, SARS-CoV-1, and HIV-1 derived ssRNA sequences ac... | KEEP AS NON CORE | Summary: IDA: TLR8/MYD88 responses to viral RNA. Reason: The paper measures cytokine output, an antiviral-relevant response rather than viral restriction; non-core. Supporting Evidence: PMID:33718825 Thus the TLR8/MYD88 pathway is required for viral GU-rich RNA-induced IL-1Ξ², TNF, and IL-6 expression from human macrophages |
| GO:0060090 molecular adaptor activity | IDA PMID:16751103 Phosphoinositide-mediated adaptor recruitment controls Toll-... | MODIFY | Summary: IDA molecular adaptor activity (TLR4/TIRAP study). Reason: Correct but general; the child GO:0035591 signaling adaptor activity is the precise MF, as used in the TLR4 GO-CAM. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. |
| GO:0060090 molecular adaptor activity | IDA PMID:9430229 MyD88: an adapter that recruits IRAK to the IL-1 receptor co... | MODIFY | Summary: IDA molecular adaptor activity: MyD88 couples IRAK to IL-1R. Reason: Replace with signaling adaptor activity. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:9430229 MyD88 binds to both IRAK (IL-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of IRAK with the receptor. PMID:9430229 it couples a serine/threonine protein kinase to the receptor complex. |
| GO:0060090 molecular adaptor activity | IDA PMID:9734363 MyD88 is an adaptor protein in the hToll/IL-1 receptor famil... | MODIFY | Summary: IDA molecular adaptor activity for human Toll (TLR4) signalling. Reason: Replace with signaling adaptor activity. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:9734363 We now demonstrate that signaling by the human Toll receptor employs an adaptor protein, MyD88, and induces activation of NF-kappaB via the Pelle-like kinase IRAK and the TRAF6 protein, similar to IL-1R-mediated NF-kappaB activation. |
| GO:0060337 type I interferon-mediated signaling pathway | IMP PMID:23633945 HCV-induced miR-21 contributes to evasion of host immune sys... | MARK AS OVER ANNOTATED | Summary: IMP: miR-21 targeting of MyD88 reduces type I IFN effector gene expression in HCV infection. Reason: MYD88 acts in TLR signalling upstream of type I IFN production, not in the IFNAR-JAK-STAT pathway. The reduced IFN effector gene expression follows from reduced IFN production; the sibling annotation to positive regulation of type I interferon production captures the finding. Supporting Evidence: PMID:23633945 Upregulated miR-21 suppressed MyD88 and IRAK1 expression in hepatocytes, which subsequently repressed type I IFN effector gene expression and the type I IFN-mediated antiviral response, thereby promoting viral replication. PMID:23633945 Furthermore, we demonstrated that miR-21 targets two important factors in the TLR signaling pathway, myeloid differentiation factor 88 (MyD88) and interleukin-1 receptor-associated kinase 1 (IRAK1), which are involved in HCV-induced type I IFN production. |
| GO:0070498 interleukin-1-mediated signaling pathway | IDA PMID:9430229 MyD88: an adapter that recruits IRAK to the IL-1 receptor co... | ACCEPT | Summary: IDA: MyD88 is recruited to the IL-1 receptor complex and couples IRAK to it. Reason: Core process. Supporting Evidence: PMID:9430229 MyD88 binds to both IRAK (IL-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of IRAK with the receptor. PMID:9430229 Here we show that MyD88, a previously described protein of unknown function, is recruited to the IL-1 receptor complex following IL-1 stimulation. |
| GO:0070498 interleukin-1-mediated signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer (mouse): interleukin-1-mediated signaling pathway. Reason: Core. Supporting Evidence: PMID:9430229 Here we show that MyD88, a previously described protein of unknown function, is recruited to the IL-1 receptor complex following IL-1 stimulation. |
| GO:0070498 interleukin-1-mediated signaling pathway | NAS PMID:36865541 Regulation of innate immune signaling by IRAK proteins. | ACCEPT | Summary: NAS (IRAK review): IL-1 signaling. Reason: Core. Supporting Evidence: PMID:36865541 Signaling via most TLRs and IL-1Rs is mediated by the protein myeloid differentiation primary-response protein 88 (MyD88). |
| GO:0070555 response to interleukin-1 | IMP PMID:19281832 Activation of ROS/NF-kappaB and Ca2+/CaM kinase II are neces... | KEEP AS NON CORE | Summary: IMP: MyD88 siRNA blocks IL-1beta-induced VCAM-1 in airway smooth muscle cells. Reason: Consistent with the IL-1 pathway role (already accepted); this cellular-response term is non-core. Supporting Evidence: PMID:19281832 IL-1beta stimulated NF-kappaB and CaMKII phosphorylation through MyD88-dependent PI-PLC/PKCalpha/c-Src/ROS and PI-PLC/Ca2+/CaM pathways, respectively. |
| GO:0070935 3'-UTR-mediated mRNA stabilization | IDA PMID:15294994 Toll IL-1 receptors differ in their ability to promote the s... | KEEP AS NON CORE | Summary: IDA: MyD88 overexpression promotes stabilization of ARE-containing mRNAs. Reason: An indirect downstream effect of MyD88 signalling (p38/MK2 pathway), not an RNA-binding activity of MYD88. Supporting Evidence: PMID:15294994 Overexpression of MyD88 or MyD88 adaptor-like protein was able to promote enhanced stability of ARE-containing mRNA, whereas Trif and Trif-related adaptor molecule exhibited markedly reduced capacity. |
| GO:0070976 TIR domain binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro IEA: TIR domain binding. Reason: Core: MYD88 TIR domain binds TIR domains of TLRs, IL-1R and TIRAP. Supporting Evidence: PMID:17258210 We show that the TLR adaptor Mal is critical for linking Myeloid Differentiation primary response protein 88 (MyD88) to TLR2 and TLR4. PMID:11544529 Mal can form homodimers and can also form heterodimers with MyD88. |
| GO:0070976 TIR domain binding | IPI PMID:19509286 A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP resul... | ACCEPT | Summary: IPI: TIRAP D96N variant cannot bind MyD88. Reason: Core TIR-TIR interaction. Supporting Evidence: PMID:19509286 Moreover, co-immunoprecipitation studies revealed that Mal D96N is unable to interact with MyD88, a prerequisite for downstream signaling to occur. |
| GO:0071222 cellular response to lipopolysaccharide | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer (rat): cellular response to LPS. Reason: Correct via the TLR4-MyD88 arm. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. |
| GO:0071222 cellular response to lipopolysaccharide | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse: cellular response to LPS. Reason: Correct. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. |
| GO:0071260 cellular response to mechanical stimulus | IEP PMID:19593445 Expression of the Bcl-2 protein BAD promotes prostate cancer... | UNDECIDED | Summary: IEP: cellular response to mechanical stimulus, citing a paper on BAD in prostate cancer. Reason: The cached full text of PMID:19593445 does not mention MyD88, TLRs, or mechanical stimulation; the reference may be incorrect. Without the curator's source this cannot be verified. |
| GO:0140052 cellular response to oxidised low-density lipoprotein particle stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer (mouse): cellular response to oxidised LDL. Reason: OxLDL signals via TLR4/TLR2-MyD88 in mouse macrophages; non-core cellular response. |
| GO:0140052 cellular response to oxidised low-density lipoprotein particle stimulus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: cellular response to oxidised LDL. Reason: As above. |
| GO:0140674 ATP-dependent histone chaperone activity | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl transfer (mouse): ATP-dependent histone chaperone activity. Reason: The mouse source is an IMP from PMID:18319258 showing that MyD88 signalling is required for nucleosome remodeling at secondary-response promoters. That is an indirect transcriptional consequence; MYD88 is a cytoplasmic adaptor with no ATPase or histone-binding activity. The molecular-function annotation (and its inferred chromatin-remodeling process) is a misapplication of a phenotype. Supporting Evidence: PMID:18319258 This selective dependence correlates with the fact that MyD88 is required for nucleosome remodeling and histone H3K4 trimethylation at secondary response promoters |
| GO:1900017 positive regulation of cytokine production involved in inflammatory response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer (mouse): positive regulation of cytokine production involved in inflammatory response. Reason: Downstream output. Supporting Evidence: PMID:33718825 Thus the TLR8/MYD88 pathway is required for viral GU-rich RNA-induced IL-1Ξ², TNF, and IL-6 expression from human macrophages |
| GO:1900017 positive regulation of cytokine production involved in inflammatory response | IMP PMID:20219467 Identification of MyD88 as a novel target of miR-155, involv... | KEEP AS NON CORE | Summary: IMP: miR-155/MyD88/IL-8. Reason: Downstream output. Supporting Evidence: PMID:20219467 Furthermore, the overexpression of miR-155 led to significantly reduced IL-8 production induced by H. pylori infection. |
| GO:1900017 positive regulation of cytokine production involved in inflammatory response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: positive regulation of cytokine production involved in inflammatory response. Reason: Downstream output. Supporting Evidence: PMID:33718825 Thus the TLR8/MYD88 pathway is required for viral GU-rich RNA-induced IL-1Ξ², TNF, and IL-6 expression from human macrophages |
| GO:1900227 positive regulation of NLRP3 inflammasome complex assembly | IMP PMID:33718825 SARS-CoV-2, SARS-CoV-1, and HIV-1 derived ssRNA sequences ac... | KEEP AS NON CORE | Summary: IMP: TLR8/MYD88 required for NLRP3 activation by viral GU-rich RNA. Reason: MYD88 supplies the TLR8 priming signal; a regulatory, non-core role. Supporting Evidence: PMID:33718825 With the use of inhibitors and RNAi, we also demonstrate that activation of the NLRP3 inflammasome by GU-rich RNA is specifically TLR8-dependent and RNA-mediated, leading to CASP1 activation and the conversion of pro-IL-1Ξ² to its active form. PMID:33718825 Thus the TLR8/MYD88 pathway is required for viral GU-rich RNA-induced IL-1Ξ², TNF, and IL-6 expression from human macrophages |
| GO:1902554 serine/threonine protein kinase complex | NAS PMID:30256449 Understanding early TLR signaling through the Myddosome. | ACCEPT | Summary: NAS (Myddosome review): serine/threonine protein kinase complex. Reason: The Myddosome contains the IRAK4 and IRAK1/2 kinases with MYD88 as its scaffold; GO has no specific Myddosome term, so this is the most specific available complex term. Supporting Evidence: PMID:30256449 Upon activation, TLRs facilitate the assembly of large intracellular oligomeric signaling complexes, termed Myddosomes, which initiate key signal transduction pathways to elicit critical inflammatory immune responses. PMID:36865541 The myddosome is a supramolecular signaling complex assembled upon dimerization of IL-1Rs and most TLRs (except TLR3), and is composed of MyD88, IRAK4, IRAK1 and/or IRAK2, in addition to TRAF6. |
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Download this section (compressed HTML)Q: Should GO:0008063 Toll signaling pathway be removed from the MyD88-family IBD at PTN000386853 for vertebrate descendants, or restricted to the arthropod clade? GO:0008063 is defined for the receptor Toll and is not an ancestor of GO:0002224, so all vertebrate MYD88 orthologues currently inherit a Drosophila-specific pathway term.
Q: Human MYD88 is the adaptor for IL-18R1/IL18RAP signalling, but neither human MYD88 nor IRAK4 or TRAF6 is annotated to GO:0035655 interleukin-18-mediated signaling pathway (only ligand, receptor and a few kinases are). Is this a deliberate convention or a gap for the adaptor layer?
Q: The mouse Myd88 annotations to GO:0140674 ATP-dependent histone chaperone activity and GO:0006325 chromatin organization (IMP, PMID:18319258) read an indirect transcriptional phenotype as a molecular activity; should the MGI source annotations be withdrawn so that they stop propagating to human and other orthologues?
Q: Which reference supports the IEP annotation to GO:0071260 cellular response to mechanical stimulus? The cited PMID:19593445 does not mention MyD88.
Q: Would a Myddosome cellular-component term (MYD88-IRAK4-IRAK1/2 helical assembly) be useful? GO:1902554 serine/threonine protein kinase complex is currently the most specific available term.
Experiment: Endogenous-tag proteomics (as in PMID:38961291) comparing Myddosome composition after IL-18, IL-33 and IL-36 stimulation with TLR stimulation, to test whether the MYD88 scaffold recruits the same effector set across IL-1R family receptors.
Experiment: Genome-edited human macrophages lacking MYD88 (not siRNA), to test whether any phagocytosis defect exists independently of TLR4-TRAM signalling. Human siRNA and mouse knockout data currently disagree.
Experiment: Chromatin immunoprecipitation or CUT&RUN for endogenous MYD88, with a nuclear-exclusion mutant, to test whether the reported nuclear pool has any direct role at promoters or is an overexpression artefact.
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