TLR10 is a type I transmembrane receptor of the Toll-like receptor family, most closely related to TLR1 and TLR6 and encoded in the same TLR6-TLR1-TLR10 cluster; it is functional in humans but is a disrupted pseudogene in mice. It is expressed mainly in B cells, plasmacytoid dendritic cells and monocytes, on the cell surface and in endosomes. Like TLR1 it heterodimerises with TLR2, senses triacylated lipopeptides through TLR2 and recruits MYD88 through its TIR domain, but unlike other TLRs it largely fails to activate NF-kappaB. Instead TLR10 acts mainly as an inhibitory receptor: it dampens proinflammatory and type I interferon responses to other TLR agonists (MyD88- and TRIF-dependent), in part by competing for TLR2 or ligand and by PI3K/Akt-driven IL-1 receptor antagonist production; it suppresses B cell proliferation and antibody responses cell-intrinsically, restrains monocyte-to-dendritic-cell differentiation, and in pDCs induces STAT3/SOCS3 and blocks IRF7 nuclear translocation. Proposed ligands include lipopeptides, double-stranded RNA and HIV-1 gp41, and some studies report activating roles in viral and Listeria infection.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002224 toll-like receptor signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT IBA for toll-like receptor signaling pathway (TLR node PTN002808083). Reason: TLR10 is a TLR-family receptor that recruits MyD88 and, when engaged, initiates intracellular signaling, so the general term is not wrong. But the target-specific evidence departs from the positive-signaling function inherited at this node: TLR10 alone or with TLR2 fails to activate NF-kappaB, IL-8 or IFN-beta reporters, and gain- and loss-of-function studies (transfected U937 cells, TLR10 transgenic mice, blocking and cross-linking antibodies in primary human cells) show it suppresses both MyD88- and TRIF-dependent TLR responses. A minority of studies report positive sensing roles (influenza, Listeria, HIV-1 gp41). The term is kept as non-core; the core role is better captured by negative regulation of toll-like receptor signaling pathway. Supporting Evidence: PMID:15728506 by using a recombinant CD4TLR10 molecule we also demonstrated that TLR10 directly associates with MyD88 PMID:20348427 However, TLR10, alone or in cooperation with TLR2, fails to activate typical TLR-induced signaling, including NF-kappaB-, IL-8-, or IFN-beta-driven reporters PMID:27022193 These results demonstrate that TLR10 functions as a broad negative regulator of TLR signaling PMID:24567377 TLR10 contributed to innate immune sensing of viral infection leading to cytokine induction, including proinflammatory cytokines and interferons |
| GO:0002224 toll-like receptor signaling pathway | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO (IPR017241) mapping to toll-like receptor signaling pathway. Reason: TLR10 is a TLR-family receptor that recruits MyD88 and, when engaged, initiates intracellular signaling, so the general term is not wrong. But the target-specific evidence departs from the positive-signaling function inherited at this node: TLR10 alone or with TLR2 fails to activate NF-kappaB, IL-8 or IFN-beta reporters, and gain- and loss-of-function studies (transfected U937 cells, TLR10 transgenic mice, blocking and cross-linking antibodies in primary human cells) show it suppresses both MyD88- and TRIF-dependent TLR responses. A minority of studies report positive sensing roles (influenza, Listeria, HIV-1 gp41). The term is kept as non-core; the core role is better captured by negative regulation of toll-like receptor signaling pathway. Supporting Evidence: PMID:20348427 However, TLR10, alone or in cooperation with TLR2, fails to activate typical TLR-induced signaling, including NF-kappaB-, IL-8-, or IFN-beta-driven reporters PMID:27022193 These results demonstrate that TLR10 functions as a broad negative regulator of TLR signaling |
| GO:0004888 transmembrane signaling receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping to transmembrane signaling receptor activity. Reason: TLR10 is a type I transmembrane receptor; antibody engagement of its ectodomain triggers intracellular signaling (PI3K/Akt, STAT3/SOCS3), so this general receptor activity is correct regardless of the sign of the output. Supporting Evidence: PMID:11267672 it is characterized by a signal peptide followed by multiple leucine-rich repeats (LRRs), a cysteine-rich domain, a transmembrane sequence and a cytoplasmic domain homologous to that of the human interleukin-1 receptor PMID:27956526 We have found that Ab-mediated engagement of TLR10 on primary human B cells suppresses B cell proliferation, cytokine production, and signal transduction PMID:38995177 Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response |
| GO:0004888 transmembrane signaling receptor activity | TAS PMID:11267672 Identification of hTLR10: a novel human Toll-like receptor p... | ACCEPT | Summary: TAS from the cloning paper: transmembrane signaling receptor activity. Reason: Domain architecture of a TLR; later functional work shows ectodomain engagement signals into the cell. Supporting Evidence: PMID:11267672 it is characterized by a signal peptide followed by multiple leucine-rich repeats (LRRs), a cysteine-rich domain, a transmembrane sequence and a cytoplasmic domain homologous to that of the human interleukin-1 receptor PMID:27956526 We have found that Ab-mediated engagement of TLR10 on primary human B cells suppresses B cell proliferation, cytokine production, and signal transduction |
| GO:0005515 protein binding | IPI PMID:15728506 Human TLR10 is a functional receptor, expressed by B cells a... | MODIFY | Summary: IPI: TLR10 co-immunoprecipitates with TLR2. Reason: Protein binding is uninformative; heterodimerisation with TLR2 is reproducible (co-IP, agonist-dependent interaction) and is the basis of TLR10 inhibitory action. GO:0035663 Toll-like receptor 2 binding is the informative term. Proposed replacements: Toll-like receptor 2 binding Supporting Evidence: PMID:15728506 We have shown that TLR10 was not only able to homodimerize but also heterodimerized with TLRs 1 and 2 PMID:20348427 TLR10 requires TLR2 for innate immune recognition, and these receptors colocalize in the phagosome and physically interact in an agonist-dependent fashion |
| GO:0005515 protein binding | IPI PMID:15728506 Human TLR10 is a functional receptor, expressed by B cells a... | MODIFY | Summary: IPI: TLR10 co-immunoprecipitates with TLR1. Reason: Protein binding is uninformative; GO:0035325 Toll-like receptor binding describes the heterodimerisation. Physiological relevance of the TLR1:TLR10 pair is unclear (overexpression). Proposed replacements: Toll-like receptor binding Supporting Evidence: PMID:15728506 We have shown that TLR10 was not only able to homodimerize but also heterodimerized with TLRs 1 and 2 |
| GO:0005515 protein binding | IPI PMID:23155421 Isolated Toll-like receptor transmembrane domains are capabl... | REMOVE | Summary: IPI: TLR10 and TLR2 transmembrane domains interact in an E. coli ToxR reporter. Reason: Protein binding is uninformative; isolated-TMD bacterial assay only. The TLR2 interaction is represented (as Toll-like receptor 2 binding) from co-immunoprecipitation evidence. Supporting Evidence: PMID:23155421 The TLR2 transmembrane domain demonstrated strong heterotypic interactions in bacterial membranes with its known interaction partners, TLR1 and TLR6, as well as with a proposed interaction partner, TLR10 |
| GO:0005515 protein binding | IPI PMID:23155421 Isolated Toll-like receptor transmembrane domains are capabl... | REMOVE | Summary: IPI: TLR10 and TLR1 transmembrane domains interact in an E. coli ToxR reporter. Reason: Protein binding is uninformative; isolated-TMD bacterial assay only. Supporting Evidence: PMID:23155421 The TLR2 transmembrane domain demonstrated strong heterotypic interactions in bacterial membranes with its known interaction partners, TLR1 and TLR6, as well as with a proposed interaction partner, TLR10 |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: IPI from a neurodegenerative-disease yeast two-hybrid interactome: TLR10 with WFS1. Reason: High-throughput Y2H hit of an ER membrane protein with no functional follow-up; protein binding is uninformative. Supporting Evidence: PMID:32814053 generated by systematic yeast two-hybrid interaction screening of βΌ500 ND-related proteins |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: IPI from a neurodegenerative-disease yeast two-hybrid interactome: TLR10 with ATXN3. Reason: High-throughput Y2H hit with no functional follow-up; protein binding is uninformative. Supporting Evidence: PMID:32814053 generated by systematic yeast two-hybrid interaction screening of βΌ500 ND-related proteins |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA: plasma membrane (is_active_in). Reason: TLR10 is found on the surface of pDCs, B cells and monocytes, where antibody engagement triggers its inhibitory signaling. It is also reported in endosomes of macrophages. Supporting Evidence: PMID:38995177 Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response PMID:28235773 We report that TLR10 is preferentially expressed on monocytes and suppresses proinflammatory cytokine production resulting from either TLR or CD40 stimulation |
| GO:0005886 plasma membrane | NAS PMID:33576548 Structural and functional understanding of the toll-like rec... | ACCEPT | Summary: NAS from a TLR structural review. Reason: Review groups TLR10 with the cell-membrane TLRs. Supporting Evidence: PMID:33576548 One group is composed of TLR1, TLR2, TLR4, TLR5, TLR6 and poorly characterized TLR10, which are localized to cell membranes and predominantly recognize bacterial components such as lipids, lipoproteins, and proteins. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-168947 | ACCEPT | Summary: Reactome places TLR10 at the plasma membrane in its TLR5/TLR10 MyD88-IRAK reactions. Reason: The location is supported: TLR10 is constitutively on the surface of pDCs (it is also found in endosomes in macrophages). The Reactome reactions themselves model TLR10 as an activating receptor, which the experimental literature largely does not support, but that does not affect this cellular component annotation. Supporting Evidence: PMID:38995177 Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602603 | ACCEPT | Summary: Reactome places TLR10 at the plasma membrane in its TLR5/TLR10 MyD88-IRAK reactions. Reason: The location is supported: TLR10 is constitutively on the surface of pDCs (it is also found in endosomes in macrophages). The Reactome reactions themselves model TLR10 as an activating receptor, which the experimental literature largely does not support, but that does not affect this cellular component annotation. Supporting Evidence: PMID:38995177 Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975852 | ACCEPT | Summary: Reactome places TLR10 at the plasma membrane in its TLR5/TLR10 MyD88-IRAK reactions. Reason: The location is supported: TLR10 is constitutively on the surface of pDCs (it is also found in endosomes in macrophages). The Reactome reactions themselves model TLR10 as an activating receptor, which the experimental literature largely does not support, but that does not affect this cellular component annotation. Supporting Evidence: PMID:38995177 Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975853 | ACCEPT | Summary: Reactome places TLR10 at the plasma membrane in its TLR5/TLR10 MyD88-IRAK reactions. Reason: The location is supported: TLR10 is constitutively on the surface of pDCs (it is also found in endosomes in macrophages). The Reactome reactions themselves model TLR10 as an activating receptor, which the experimental literature largely does not support, but that does not affect this cellular component annotation. Supporting Evidence: PMID:38995177 Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975857 | ACCEPT | Summary: Reactome places TLR10 at the plasma membrane in its TLR5/TLR10 MyD88-IRAK reactions. Reason: The location is supported: TLR10 is constitutively on the surface of pDCs (it is also found in endosomes in macrophages). The Reactome reactions themselves model TLR10 as an activating receptor, which the experimental literature largely does not support, but that does not affect this cellular component annotation. Supporting Evidence: PMID:38995177 Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975861 | ACCEPT | Summary: Reactome places TLR10 at the plasma membrane in its TLR5/TLR10 MyD88-IRAK reactions. Reason: The location is supported: TLR10 is constitutively on the surface of pDCs (it is also found in endosomes in macrophages). The Reactome reactions themselves model TLR10 as an activating receptor, which the experimental literature largely does not support, but that does not affect this cellular component annotation. Supporting Evidence: PMID:38995177 Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975865 | ACCEPT | Summary: Reactome places TLR10 at the plasma membrane in its TLR5/TLR10 MyD88-IRAK reactions. Reason: The location is supported: TLR10 is constitutively on the surface of pDCs (it is also found in endosomes in macrophages). The Reactome reactions themselves model TLR10 as an activating receptor, which the experimental literature largely does not support, but that does not affect this cellular component annotation. Supporting Evidence: PMID:38995177 Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975866 | ACCEPT | Summary: Reactome places TLR10 at the plasma membrane in its TLR5/TLR10 MyD88-IRAK reactions. Reason: The location is supported: TLR10 is constitutively on the surface of pDCs (it is also found in endosomes in macrophages). The Reactome reactions themselves model TLR10 as an activating receptor, which the experimental literature largely does not support, but that does not affect this cellular component annotation. Supporting Evidence: PMID:38995177 Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975873 | ACCEPT | Summary: Reactome places TLR10 at the plasma membrane in its TLR5/TLR10 MyD88-IRAK reactions. Reason: The location is supported: TLR10 is constitutively on the surface of pDCs (it is also found in endosomes in macrophages). The Reactome reactions themselves model TLR10 as an activating receptor, which the experimental literature largely does not support, but that does not affect this cellular component annotation. Supporting Evidence: PMID:38995177 Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975874 | ACCEPT | Summary: Reactome places TLR10 at the plasma membrane in its TLR5/TLR10 MyD88-IRAK reactions. Reason: The location is supported: TLR10 is constitutively on the surface of pDCs (it is also found in endosomes in macrophages). The Reactome reactions themselves model TLR10 as an activating receptor, which the experimental literature largely does not support, but that does not affect this cellular component annotation. Supporting Evidence: PMID:38995177 Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975878 | ACCEPT | Summary: Reactome places TLR10 at the plasma membrane in its TLR5/TLR10 MyD88-IRAK reactions. Reason: The location is supported: TLR10 is constitutively on the surface of pDCs (it is also found in endosomes in macrophages). The Reactome reactions themselves model TLR10 as an activating receptor, which the experimental literature largely does not support, but that does not affect this cellular component annotation. Supporting Evidence: PMID:38995177 Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975879 | ACCEPT | Summary: Reactome places TLR10 at the plasma membrane in its TLR5/TLR10 MyD88-IRAK reactions. Reason: The location is supported: TLR10 is constitutively on the surface of pDCs (it is also found in endosomes in macrophages). The Reactome reactions themselves model TLR10 as an activating receptor, which the experimental literature largely does not support, but that does not affect this cellular component annotation. Supporting Evidence: PMID:38995177 Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975880 | ACCEPT | Summary: Reactome places TLR10 at the plasma membrane in its TLR5/TLR10 MyD88-IRAK reactions. Reason: The location is supported: TLR10 is constitutively on the surface of pDCs (it is also found in endosomes in macrophages). The Reactome reactions themselves model TLR10 as an activating receptor, which the experimental literature largely does not support, but that does not affect this cellular component annotation. Supporting Evidence: PMID:38995177 Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response |
| GO:0006955 immune response | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO mapping to immune response. Reason: Correct but very general; TLR10 regulates innate and humoral immune responses. Supporting Evidence: PMID:27956526 Adoptive transfer of splenic B cells into B cell-deficient mice revealed that the suppressive effects on Ag-specific humoral immune responses are entirely B cell intrinsic |
| GO:0006955 immune response | NAS PMID:11267672 Identification of hTLR10: a novel human Toll-like receptor p... | KEEP AS NON CORE | Summary: NAS from the cloning paper: immune response. Reason: Based on immune-tissue expression; later work shows TLR10 modulates immune responses. Supporting Evidence: PMID:11267672 hTLR10 is preferentially expressed in tissues and cells involved in immune responses PMID:25288745 We demonstrate that TLR10 is a modulatory receptor with mainly inhibitory effects |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO (TIR domain) mapping to signal transduction. Reason: Correct but uninformative. Supporting Evidence: PMID:27956526 We have found that Ab-mediated engagement of TLR10 on primary human B cells suppresses B cell proliferation, cytokine production, and signal transduction |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA: membrane. Reason: Single-pass type I membrane protein. Supporting Evidence: PMID:11267672 it is characterized by a signal peptide followed by multiple leucine-rich repeats (LRRs), a cysteine-rich domain, a transmembrane sequence and a cytoplasmic domain homologous to that of the human interleukin-1 receptor |
| GO:0016020 membrane | TAS PMID:11267672 Identification of hTLR10: a novel human Toll-like receptor p... | ACCEPT | Summary: TAS: membrane. Reason: Correct. Supporting Evidence: PMID:11267672 it is characterized by a signal peptide followed by multiple leucine-rich repeats (LRRs), a cysteine-rich domain, a transmembrane sequence and a cytoplasmic domain homologous to that of the human interleukin-1 receptor |
| GO:0035663 Toll-like receptor 2 binding | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA: Toll-like receptor 2 binding (TLR1/TLR6/TLR10 clade node PTN000687445). Reason: Confirmed on TLR10 itself by co-IP and agonist-dependent interaction; TLR2 heterodimerisation underlies both its lipopeptide sensing and its inhibition of TLR2 responses. Supporting Evidence: PMID:15728506 We have shown that TLR10 was not only able to homodimerize but also heterodimerized with TLRs 1 and 2 PMID:20348427 TLR10 requires TLR2 for innate immune recognition, and these receptors colocalize in the phagosome and physically interact in an agonist-dependent fashion PMID:25288745 cotransfection in human cell lines showed that TLR10 acts as an inhibitory receptor when forming heterodimers with TLR2 |
| GO:0038023 signaling receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA: signaling receptor activity. Reason: General receptor activity is correct (see transmembrane signaling receptor activity). Supporting Evidence: PMID:27956526 We have found that Ab-mediated engagement of TLR10 on primary human B cells suppresses B cell proliferation, cytokine production, and signal transduction |
| GO:0042802 identical protein binding | IPI PMID:15728506 Human TLR10 is a functional receptor, expressed by B cells a... | KEEP AS NON CORE | Summary: IPI: TLR10 homodimerisation in co-immunoprecipitation. Reason: Homodimerisation shown on overexpression; functional significance not established. Supporting Evidence: PMID:15728506 We have shown that TLR10 was not only able to homodimerize but also heterodimerized with TLRs 1 and 2 |
| GO:0042802 identical protein binding | IPI PMID:23155421 Isolated Toll-like receptor transmembrane domains are capabl... | KEEP AS NON CORE | Summary: IPI: TLR10 TMD homotypic interaction in an E. coli ToxR reporter. Reason: Consistent with the co-IP homodimer; isolated-TMD evidence only, functional significance not established. Supporting Evidence: PMID:23155421 All TLR transmembrane domains showed strong homotypic interaction |
| GO:0043235 signaling receptor complex | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA IEA: signaling receptor complex. Reason: TLR10 forms agonist-dependent complexes with TLR2 that recruit MyD88; general term, non-core. Supporting Evidence: PMID:20348427 TLR10 requires TLR2 for innate immune recognition, and these receptors colocalize in the phagosome and physically interact in an agonist-dependent fashion |
| GO:0043235 signaling receptor complex | IPI PMID:23155421 Isolated Toll-like receptor transmembrane domains are capabl... | KEEP AS NON CORE | Summary: IPI: TMD oligomerisation supports signaling receptor complex. Reason: Weak (isolated TMD) evidence for a true general statement. Supporting Evidence: PMID:23155421 The TLR2 transmembrane domain demonstrated strong heterotypic interactions in bacterial membranes with its known interaction partners, TLR1 and TLR6, as well as with a proposed interaction partner, TLR10 |
| GO:0045087 innate immune response | NAS PMID:33576548 Structural and functional understanding of the toll-like rec... | KEEP AS NON CORE | Summary: NAS from a TLR structural review: innate immune response. Reason: TLR10 acts in innate immunity mainly as a negative regulator of responses initiated by other TLRs. Supporting Evidence: PMID:25288745 We demonstrate that TLR10 is a modulatory receptor with mainly inhibitory effects PMID:27022193 These results demonstrate that TLR10 functions as a broad negative regulator of TLR signaling |
| GO:0071221 cellular response to bacterial lipopeptide | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT IBA: cellular response to bacterial lipopeptide. Reason: Supported for TLR10 itself: its ectodomain senses triacylated lipopeptides with TLR2, and blocking TLR10 enhances cytokine output to the TLR2/1 ligand Pam3Cys. The response it mediates is modulatory rather than activating. Supporting Evidence: PMID:20348427 TLR10 senses triacylated lipopeptides and a wide variety of other microbial-derived agonists shared by TLR1, but not TLR6 PMID:25288745 Blocking TLR10 by antagonistic antibodies enhanced proinflammatory cytokine production, including IL-1Ξ², specifically after exposure to TLR2 ligands |
| GO:0071723 lipopeptide binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT IBA: lipopeptide binding. Reason: Plausible and consistent with TLR10-specific data: TLR10 ectodomain chimeras sense triacylated lipopeptides and modelling shows a conserved lipopeptide-binding channel. Direct binding has not been measured biochemically, and dsRNA and HIV-1 gp41 have also been proposed as ligands, so ligand identity remains open. Supporting Evidence: PMID:20348427 TLR10 senses triacylated lipopeptides and a wide variety of other microbial-derived agonists shared by TLR1, but not TLR6 PMID:20348427 Computational modeling and mutational analysis of TLR10 showed preservation of the essential TLR2 dimer interface and lipopeptide-binding channel found in TLR1 |
| GO:0034122 negative regulation of toll-like receptor signaling pathway | IDA PMID:27022193 TLR10 Is a Negative Regulator of Both MyD88-Dependent and -I... | NEW | Summary: TLR10 suppresses cytokine responses to multiple TLR agonists. Reason: TLR10 performs the regulatory step itself: stable expression in U937 cells suppresses MyD88- and TRIF-dependent signaling upstream of IkappaB and MAPK activation, TLR10 transgenic mice produce less cytokine after LPS, blocking antibodies enhance TLR2-ligand responses in human PBMC, and TLR10 inhibits as a heterodimer with TLR2. Comparators: other membrane regulators such as TYRO3 and SMPDL3B carry GO:0034122 in human GOA. Supporting Evidence: PMID:27022193 This broad TLR suppressive activity affects both MyD88- and TRIF-inducing IFN-Ξ²-mediated signaling pathways upstream of IΞΊB and MAPK activation PMID:27022193 These results demonstrate that TLR10 functions as a broad negative regulator of TLR signaling PMID:25288745 We demonstrate that TLR10 is a modulatory receptor with mainly inhibitory effects PMID:25288745 cotransfection in human cell lines showed that TLR10 acts as an inhibitory receptor when forming heterodimers with TLR2 file:human/TLR10/TLR10-deep-research-falcon.md TLR10 is characterized as a negative regulator of innate immune signaling, particularly of TLR2-driven responses |
| GO:0030889 negative regulation of B cell proliferation | IDA PMID:27956526 TLR10 Is a B Cell Intrinsic Suppressor of Adaptive Immune Re... | NEW | Summary: Antibody engagement of TLR10 on primary human B cells suppresses proliferation; the effect is B-cell intrinsic in TLR10 transgenic mice. Reason: Direct B-cell-intrinsic evidence in primary human cells and adoptive transfer of transgenic B cells; TLR10 is the receptor transducing the inhibitory signal. Supporting Evidence: PMID:27956526 We have found that Ab-mediated engagement of TLR10 on primary human B cells suppresses B cell proliferation, cytokine production, and signal transduction PMID:27956526 Adoptive transfer of splenic B cells into B cell-deficient mice revealed that the suppressive effects on Ag-specific humoral immune responses are entirely B cell intrinsic |
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Download this section (compressed HTML)Q: PAINT places toll-like receptor signaling pathway, lipopeptide binding and cellular response to bacterial lipopeptide at nodes that include TLR10. Given that TLR10 fails to activate NF-kappaB and acts mainly as a negative regulator, should PAINT record a divergence for TLR10 at the signaling-pathway node, or is the generic pathway term acceptable for a receptor that transduces an inhibitory signal?
Q: Reactome models TLR10 with TLR5 as an activating receptor for MyD88-IRAK4-IRAK1/2-TRAF6 reactions (e.g. R-HSA-975866, R-HSA-975873). Is there direct evidence for TLR10-driven IRAK activation, or should these reactions be revised in light of the inhibitory data?
Q: What is the physiological ligand of TLR10? Lipopeptides (with TLR2), dsRNA (endosomal), HIV-1 gp41 and influenza RNP have each been proposed from single laboratories; none has been confirmed by direct binding measurements from an independent group.
Q: Does GO need a molecular function term for an inhibitory pattern recognition receptor, i.e. a receptor that binds a PAMP and transmits a signal that suppresses innate immune activation, analogous to how GO:0038187 is defined for activating receptors?
Q: Antibody-mediated TLR10 engagement suppressed virus-induced IFN-alpha, IFN-lambda and TNF-alpha in primary human pDCs (PMID:38995177). Should TLR10 carry GO:0032687 negative regulation of interferon-alpha production, or is surrogate-agonist antibody engagement insufficient without an identified physiological ligand?
Experiment: Generate TLR10-knockout primary human B cells and monocytes (CRISPR RNP) and measure responses to TLR2/1, TLR4, TLR7 and TLR9 agonists and to B-cell receptor stimulation, comparing to the antibody-engagement and transgenic-mouse data.
Hypothesis: Loss of endogenous TLR10 in human cells enhances responses to other TLR agonists, confirming the negative-regulator role without relying on antibodies or overexpression.
Type: CRISPR knockout in primary human cells
Experiment: Measure direct binding of purified TLR10 ectodomain (alone and with TLR2) to Pam3CSK4, dsRNA and HIV-1 gp41 by SPR or ITC, and solve a TLR10 ectodomain structure with any confirmed ligand.
Hypothesis: At least one proposed ligand binds TLR10 directly with physiologically relevant affinity.
Type: biophysical binding assay / structural biology
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