TIRAP (TIR domain-containing adapter protein; also called Mal, MyD88-adapter-like) is a 221-residue cytoplasmic signaling adaptor of the innate immune system, consisting of a disordered N-terminal region carrying a phosphatidylinositol 4,5-bisphosphate (PIP2)-binding motif and a C-terminal Toll/interleukin-1 receptor (TIR) domain. Through PIP2 binding TIRAP is pre-positioned on the cytoplasmic face of the plasma membrane, where its TIR domain engages the TIR domains of activated TLR4 and TLR2 (with TLR1 or TLR6) and recruits the adaptor MyD88; it therefore acts as a bridging or sorting adaptor for the MyD88-dependent branch of TLR2 and TLR4 signaling, leading via IRAK kinases and TRAF6 to activation of NF-kappaB, JNK and ERK and to production of inflammatory cytokines such as TNF and IL-6. TIRAP is not required for TRIF-dependent signaling (TLR3, or the IFN-beta branch of TLR4) or for TLR7 and TLR9 responses in knockout mice. TIRAP also binds the phosphorylated cytoplasmic tail of RAGE (AGER) and the PI3K regulatory subunit p85alpha, and its activity is regulated by BTK and IRAK phosphorylation and by ubiquitin-mediated degradation. The common S180L variant, which attenuates TLR2 binding and signaling, has been associated with altered susceptibility to invasive bacterial disease, malaria and tuberculosis, and the TIR domain is a target of bacterial TIR-domain mimics such as Brucella TcpB.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | TAS PMID:19509286 A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP resul... | ACCEPT | Summary: TIRAP acts in the MyD88-dependent branch of TLR2 and TLR4 signaling as the sorting adaptor that recruits MyD88 to the activated receptor. Reason: Core process. Mal/TIRAP is required for MyD88-dependent signaling from TLR2 and TLR4 but not for the TRIF-dependent branch. Supporting Evidence: PMID:19509286 The adapter protein Mal/TIRAP (hereafter referred to as Mal) is involved in the MyD88-dependent pathway downstream of TLR2 and TLR4 PMID:12447441 Instead, TIRAP has a crucial role in the MyD88-dependent signalling pathway shared by TLR2 and TLR4. |
| GO:0005080 protein kinase C binding | IPI PMID:17161867 Protein kinase Cdelta binds TIRAP/Mal to participate in TLR ... | KEEP AS NON CORE | Summary: TIRAP binds PKCdelta via its TIR domain; PKCdelta depletion blunts TLR2/TLR4 signaling. Reason: Specific, experimentally supported interaction, but a regulatory input rather than the defining activity of TIRAP. Supporting Evidence: PMID:17161867 Truncation mutants of TIRAP/Mal showed that the TIR domain of TIRAP/Mal is responsible for binding. PMID:17161867 These results suggest that PKCdelta binding to TIRAP/Mal promotes TLR signaling events. |
| GO:0005515 protein binding | IPI PMID:11544529 Mal (MyD88-adapter-like) is required for Toll-like receptor-... | MODIFY | Summary: Mal/TIRAP co-immunoprecipitates with TLR4 through TIR-TIR contacts (Fitzgerald et al. 2001). Reason: The interaction is the receptor-proximal step of TIRAP function and is captured by the specific MF term Toll-like receptor 4 binding; generic protein binding is uninformative. Proposed replacements: Toll-like receptor 4 binding Supporting Evidence: PMID:11544529 Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction. |
| GO:0005515 protein binding | IPI PMID:11544529 Mal (MyD88-adapter-like) is required for Toll-like receptor-... | MODIFY | Summary: Mal associates with IRAK2 through its TIR domain, and NF-kB activation by Mal requires IRAK2. Reason: The partner is a protein kinase and the paper supports a specific TIR-mediated association with IRAK2; protein kinase binding is more informative than protein binding. Proposed replacements: protein kinase binding Supporting Evidence: PMID:11544529 Activation of NF-kappaB by Mal requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TIR domain. |
| GO:0005515 protein binding | IPI PMID:11544529 Mal (MyD88-adapter-like) is required for Toll-like receptor-... | MODIFY | Summary: Mal heterodimerizes with MyD88; this is the basis of its adaptor function in TLR4 signaling. Reason: No MyD88-binding MF term exists. The interaction with MyD88 is the output side of TIRAP's bridging (sorting) adaptor role, which the paper concludes explicitly; signaling adaptor activity captures this. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:11544529 Mal can form homodimers and can also form heterodimers with MyD88. PMID:11544529 Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction. |
| GO:0005515 protein binding | IPI PMID:17258210 MAPPIT analysis of TLR adaptor complexes. | MODIFY | Summary: MAPPIT two-hybrid analysis detected Mal-TLR4 interaction and showed Mal links MyD88 to TLR4. Reason: Specific receptor interaction; replace with Toll-like receptor 4 binding. Proposed replacements: Toll-like receptor 4 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. |
| GO:0005515 protein binding | IPI PMID:17258210 MAPPIT analysis of TLR adaptor complexes. | MODIFY | Summary: MAPPIT analysis showed Mal hetero-dimerizes with MyD88 and is critical for linking MyD88 to TLR2/TLR4. Reason: The paper directly supports a bridging adaptor function, so signaling adaptor activity is the informative replacement. Proposed replacements: signaling adaptor activity 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 provides an initial mechanistic insight in this bridging function of Mal. |
| GO:0005515 protein binding | IPI PMID:17583698 Distinct roles of TIR and non-TIR regions in the subcellular... | REMOVE | Summary: Interaction with MyD88 reported in a study of MyD88 subcellular localization domains. Reason: Generic protein binding; the paper concerns MyD88 localization determinants and does not add a TIRAP-specific functional insight beyond the MyD88 interaction already represented by signaling adaptor activity. Removal does not dispute the interaction. 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:19509286 A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP resul... | MODIFY | Summary: Wild-type Mal co-immunoprecipitates with MyD88, and the D96N variant that fails to bind MyD88 is signaling-dead. Reason: The paper ties MyD88 binding directly to the bridging adaptor function of Mal; signaling adaptor activity is the informative replacement. Proposed replacements: signaling adaptor activity 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. PMID:19509286 It acts as a bridging adapter between the receptor and the sorting adapter MyD88 |
| GO:0005515 protein binding | IPI PMID:19574958 Mal connects TLR2 to PI3Kinase activation and phagocyte pola... | MODIFY | Summary: Mal directly and inducibly binds the PI3K regulatory subunit p85alpha (PIK3R1) after TLR2/6 stimulation. Reason: A specific MF term exists for this interaction. Proposed replacements: phosphatidylinositol 3-kinase regulatory subunit binding Supporting Evidence: PMID:19574958 On stimulation of the TLR2/6 heterodimer with diacylated bacterial lipoproteins, Mal directly interacts with the regulatory subunit of phosphoinositide 3-kinase (PI3K), p85alpha, in an inducible fashion. |
| GO:0005515 protein binding | IPI PMID:19948740 AIP1 functions as Arf6-GAP to negatively regulate TLR4 signa... | REMOVE | Summary: TIRAP-MyD88 interaction within the TLR4-TIRAP-MyD88 complex, examined in a study of the Arf6-GAP AIP1. Reason: Generic protein binding; the MyD88 interaction is better captured by signaling adaptor activity supported elsewhere. Removal does not dispute the interaction. 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:21334391 The hepatitis B e antigen (HBeAg) targets and suppresses act... | REMOVE | Summary: Mal-MyD88 interaction examined as a target of hepatitis B e antigen interference. Reason: Generic protein binding in a viral-evasion study; the informative MyD88 relationship is represented by signaling adaptor activity. Removal does not dispute the interaction. 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: TIRAP co-precipitates with ligand-activated TLR4. Reason: Specific receptor interaction; replace with Toll-like receptor 4 binding. Proposed replacements: Toll-like receptor 4 binding Supporting Evidence: PMID:21829704 RAGE was co-precipitated with TIRAP, MyD88 and IRAK-4, while TLR4 was co-precipitated with TRAM in addition to the three proteins only when the receptors were activated by the ligands |
| GO:0005515 protein binding | IPI PMID:21829704 TIRAP, an adaptor protein for TLR2/4, transduces a signal fr... | MODIFY | Summary: TIRAP binds directly to the cytoplasmic domain of RAGE (AGER), with binding enhanced by PKCzeta phosphorylation of RAGE Ser391, and transduces RAGE signals. Reason: A specific MF term exists (RAGE receptor binding) and the paper reports direct binding. Proposed replacements: RAGE 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. PMID:21829704 Binding of TIRAP but not MyD88 to the cytoplasmic domain of RAGE was confirmed to be direct by an in vitro protein interaction assay using recombinant proteins (data not shown). |
| GO:0005515 protein binding | IPI PMID:21873236 Crystal structure of Toll-like receptor adaptor MAL/TIRAP re... | MODIFY | Summary: The MAL TIR-domain crystal structure identified the MyD88-interacting interface, validated by mutagenesis and co-immunoprecipitation. Reason: The paper maps the MyD88-binding surface as the basis of Mal's bridging function; signaling adaptor activity is the informative replacement. Proposed replacements: signaling adaptor activity 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:21903422 Mapping a dynamic innate immunity protein interaction networ... | MODIFY | Summary: TLR4 found as a TIRAP interactor in the HI5 innate immunity interactome. Reason: High-throughput, but the partner is the established receptor for TIRAP; the specific term Toll-like receptor 4 binding is the informative representation. Proposed replacements: Toll-like receptor 4 binding Supporting Evidence: PMID:21903422 Fifty-eight baits were associated with 260 interacting proteins forming a human innate immunity interactome for type I interferon (HI5) of 401 unique interactions |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: Generic protein binding from a high-throughput interactome screen. Reason: Uninformative protein binding annotation from a large-scale affinity-purification/mass-spectrometry interactome. Removal does not dispute the reported interaction, but the partner is not an established TIRAP signaling partner and the interaction does not support a more specific molecular function. Supporting Evidence: PMID:21903422 Fifty-eight baits were associated with 260 interacting proteins forming a human innate immunity interactome for type I interferon (HI5) of 401 unique interactions |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: Generic protein binding from a high-throughput interactome screen. Reason: Uninformative protein binding annotation from a large-scale affinity-purification/mass-spectrometry interactome. Removal does not dispute the reported interaction, but the partner is not an established TIRAP signaling partner and the interaction does not support a more specific molecular function. Supporting Evidence: PMID:21903422 Fifty-eight baits were associated with 260 interacting proteins forming a human innate immunity interactome for type I interferon (HI5) of 401 unique interactions |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: Generic protein binding from a high-throughput interactome screen. Reason: Uninformative protein binding annotation from a large-scale affinity-purification/mass-spectrometry interactome. Removal does not dispute the reported interaction, but the partner is not an established TIRAP signaling partner and the interaction does not support a more specific molecular function. Supporting Evidence: PMID:21903422 Fifty-eight baits were associated with 260 interacting proteins forming a human innate immunity interactome for type I interferon (HI5) of 401 unique interactions |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: Generic protein binding from a high-throughput interactome screen. Reason: Uninformative protein binding annotation from a large-scale affinity-purification/mass-spectrometry interactome. Removal does not dispute the reported interaction, but the partner is not an established TIRAP signaling partner and the interaction does not support a more specific molecular function. Supporting Evidence: PMID:21903422 Fifty-eight baits were associated with 260 interacting proteins forming a human innate immunity interactome for type I interferon (HI5) of 401 unique interactions |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: Generic protein binding from a high-throughput interactome screen. Reason: Uninformative protein binding annotation from a large-scale affinity-purification/mass-spectrometry interactome. Removal does not dispute the reported interaction, but the partner is not an established TIRAP signaling partner and the interaction does not support a more specific molecular function. Supporting Evidence: PMID:21903422 Fifty-eight baits were associated with 260 interacting proteins forming a human innate immunity interactome for type I interferon (HI5) of 401 unique interactions |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: Generic protein binding from a high-throughput interactome screen. Reason: Uninformative protein binding annotation from a large-scale affinity-purification/mass-spectrometry interactome. Removal does not dispute the reported interaction, but the partner is not an established TIRAP signaling partner and the interaction does not support a more specific molecular function. Supporting Evidence: PMID:21903422 Fifty-eight baits were associated with 260 interacting proteins forming a human innate immunity interactome for type I interferon (HI5) of 401 unique interactions |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: Generic protein binding from a high-throughput interactome screen. Reason: Uninformative protein binding annotation from a large-scale affinity-purification/mass-spectrometry interactome. Removal does not dispute the reported interaction, but the partner is not an established TIRAP signaling partner and the interaction does not support a more specific molecular function. Supporting Evidence: PMID:21903422 Fifty-eight baits were associated with 260 interacting proteins forming a human innate immunity interactome for type I interferon (HI5) of 401 unique interactions |
| GO:0005515 protein binding | IPI PMID:22155231 The Brucella TIR-like protein TcpB interacts with the death ... | REMOVE | Summary: Interaction with a Brucella TIR-domain protein in split-luciferase complementation assays. Reason: Host-pathogen protein binding; uninformative about TIRAP's own function (it reflects bacterial mimicry targeting the host adaptor). 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, the only other adaptor protein that detectably interacts with TcpB. |
| GO:0005515 protein binding | IPI PMID:24275656 Crystal structures of the Toll/Interleukin-1 receptor (TIR) ... | REMOVE | Summary: Brucella TcpB binds TIRAP and inhibits TLR signaling by TIR-domain mimicry. Reason: Host-pathogen protein binding; uninformative about TIRAP's own molecular function. Supporting Evidence: PMID:24275656 The TIR domain-containing protein TcpB from Brucella inhibits TLR signaling through interaction with host adaptor proteins TIRAP/Mal and MyD88. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IRAK1 interaction from a proteome-scale binary interactome screen. Reason: Uninformative high-throughput protein binding. UniProt notes that TIRAP does not interact with IRAK1 in targeted studies; Mal-driven NF-kB activation requires IRAK2 but not IRAK1. Supporting Evidence: PMID:11544529 Activation of NF-kappaB by Mal requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TIR domain. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: MyD88 interaction from a proteome-scale binary interactome screen. Reason: Uninformative high-throughput protein binding; the MyD88 relationship is captured by signaling adaptor activity from targeted studies. Removal does not dispute the interaction. |
| GO:0005546 phosphatidylinositol-4,5-bisphosphate binding | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from mouse Tirap, where Kagan and Medzhitov identified an N-terminal PIP2-binding domain that targets TIRAP to the plasma membrane. Reason: PIP2 binding is the mechanism by which TIRAP pre-positions itself at the plasma membrane to meet activated TLR4/TLR2; the human structure paper describes the same constitutive PIP2-mediated membrane association. Supporting Evidence: PMID:16751103 We find that TIRAP contains a phosphatidylinositol 4,5-bisphosphate (PIP2) binding domain, which mediates TIRAP recruitment to the plasma membrane. PMID:21873236 MAL associates constitutively with the plasma membrane through a phosphatidylinositol-4,5-bisphosphate (PIP2)-binding motif at the N terminus of the protein |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of cytoplasmic localization. Reason: TIRAP is a cytoplasmic adaptor that is peripherally associated with the inner leaflet of the plasma membrane; cytoplasm is correct at a general level. Supporting Evidence: PMID:11544529 Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction. |
| GO:0005737 cytoplasm | IDA PMID:19948740 AIP1 functions as Arf6-GAP to negatively regulate TLR4 signa... | ACCEPT | Summary: Cytoplasmic localization observed experimentally. Reason: Consistent with TIRAP being a cytoplasmic, membrane-associated adaptor. 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:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to cytoplasm. Reason: Correct at a general level. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2201316 | KEEP AS NON CORE | Summary: Reactome represents a cytosolic pool of TIRAP prior to or during recruitment to activated TLR2/TLR4. Reason: TIRAP is cytoplasmic but largely pre-associated with the plasma membrane via PIP2; cytosol is acceptable as a general location but the functional site is the cytoplasmic face of the plasma membrane. Supporting Evidence: PMID:21873236 MAL associates constitutively with the plasma membrane through a phosphatidylinositol-4,5-bisphosphate (PIP2)-binding motif at the N terminus of the protein |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2201322 | KEEP AS NON CORE | Summary: Reactome represents a cytosolic pool of TIRAP prior to or during recruitment to activated TLR2/TLR4. Reason: TIRAP is cytoplasmic but largely pre-associated with the plasma membrane via PIP2; cytosol is acceptable as a general location but the functional site is the cytoplasmic face of the plasma membrane. Supporting Evidence: PMID:21873236 MAL associates constitutively with the plasma membrane through a phosphatidylinositol-4,5-bisphosphate (PIP2)-binding motif at the N terminus of the protein |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2559414 | KEEP AS NON CORE | Summary: Reactome represents a cytosolic pool of TIRAP prior to or during recruitment to activated TLR2/TLR4. Reason: TIRAP is cytoplasmic but largely pre-associated with the plasma membrane via PIP2; cytosol is acceptable as a general location but the functional site is the cytoplasmic face of the plasma membrane. Supporting Evidence: PMID:21873236 MAL associates constitutively with the plasma membrane through a phosphatidylinositol-4,5-bisphosphate (PIP2)-binding motif at the N terminus of the protein |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2559456 | KEEP AS NON CORE | Summary: Reactome represents a cytosolic pool of TIRAP prior to or during recruitment to activated TLR2/TLR4. Reason: TIRAP is cytoplasmic but largely pre-associated with the plasma membrane via PIP2; cytosol is acceptable as a general location but the functional site is the cytoplasmic face of the plasma membrane. Supporting Evidence: PMID:21873236 MAL associates constitutively with the plasma membrane through a phosphatidylinositol-4,5-bisphosphate (PIP2)-binding motif at the N terminus of the protein |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of plasma membrane localization. Reason: TIRAP is recruited to PIP2-rich plasma membrane regions where it meets TLR4 and TLR2. Supporting Evidence: 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 | IDA PMID:16751103 Phosphoinositide-mediated adaptor recruitment controls Toll-... | ACCEPT | Summary: TIRAP localizes to the plasma membrane via its PIP2-binding domain. Reason: Direct experimental support; core location. Supporting Evidence: 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 | IDA PMID:19948740 AIP1 functions as Arf6-GAP to negatively regulate TLR4 signa... | ACCEPT | Summary: TIRAP recruits TLR4-MyD88 to PIP2-rich plasma membrane sites. Reason: Consistent with the core location. 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:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to cell membrane. Reason: Correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166072 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166082 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166091 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166119 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166284 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166286 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166362 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166363 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2201322 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2262775 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2262777 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602353 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602383 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602606 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937022 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937059 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937079 | ACCEPT | Summary: Reactome places TIRAP at the plasma membrane in TLR2/TLR4-MyD88-IRAK signaling complexes. Reason: TIRAP acts at PIP2-rich regions of the plasma membrane with activated TLR2/TLR4. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro TIR-domain mapping to signal transduction. Reason: Correct but very general; the specific TLR pathway terms carry the information. |
| GO:0007166 cell surface receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from mouse Tirap (source: IPI, PMID:11526399). Reason: Correct but general; TIRAP acts in cell-surface TLR2/TLR4 signaling, which are cell surface receptor signaling pathways. Supporting Evidence: PMID:12447441 Instead, TIRAP has a crucial role in the MyD88-dependent signalling pathway shared by TLR2 and TLR4. |
| GO:0009986 cell surface | IDA PMID:12447441 Essential role for TIRAP in activation of the signalling cas... | MODIFY | Summary: Cell surface location attributed to the Tirap knockout paper. Reason: The abstract (full text not cached) reports no localization data. TIRAP is a cytoplasmic protein that associates with the inner leaflet of the plasma membrane via PIP2; it is not exposed at the cell surface. The essence (TIRAP acts at the cell periphery with cell-surface TLRs) is correct, and the precise term is extrinsic component of cytoplasmic side of plasma membrane. Proposed replacements: extrinsic component of cytoplasmic side of plasma membrane Supporting Evidence: PMID:16751103 We find that TIRAP contains a phosphatidylinositol 4,5-bisphosphate (PIP2) binding domain, which mediates TIRAP recruitment to the plasma membrane. PMID:21873236 MAL associates constitutively with the plasma membrane through a phosphatidylinositol-4,5-bisphosphate (PIP2)-binding motif at the N terminus of the protein |
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to membrane. Reason: Correct but general. |
| GO:0030099 myeloid cell differentiation | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Transferred from mouse Tirap, whose source (PMID:11526399) reported that dominant-negative TIRAP affects TLR4-driven dendritic cell maturation. Reason: TIRAP transduces TLR signals whose downstream consequences include dendritic cell maturation; it does not act in a myeloid differentiation program. Moreover, TIRAP-deficient mice still show dendritic cell maturation after LPS. Supporting Evidence: PMID:12447441 Expression of interferon-inducible genes and the maturation of dendritic cells is observed in these mice |
| GO:0030139 endocytic vesicle | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tirap localization data (PMID:16751103). Reason: TIRAP can be found on endocytic membranes in addition to the plasma membrane; the principal site of TIRAP action with TLR4 and TLR2 is the plasma membrane. Supporting Evidence: PMID:16751103 We find that TIRAP contains a phosphatidylinositol 4,5-bisphosphate (PIP2) binding domain, which mediates TIRAP recruitment to the plasma membrane. |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:17322885 A Mal functional variant is associated with protection again... | MODIFY | Summary: Wild-type TIRAP binds TLR2, itself and MyD88 and reconstitutes TLR2 and TLR4 signaling in Tirap-deficient cells. Reason: Correct, but the more specific child term signaling adaptor activity describes TIRAP's bridging role between activated TLRs and MyD88. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:17322885 As shown in Fig. 5 upper panel, a GST-tagged version of the TIRAP 180-Leu containing allotype, unlike wild-type TIRAP, failed to bind to TLR2 PMID:17322885 Treatment of wild type MEFs with the TLR2 ligand Malp2 induced I-ΞΊBΞ± degradation at 30 and 50 minutes (first panel). This effect was absent in Tirap-deficient MEFs (second panel). |
| GO:0030674 protein-macromolecule adaptor activity | NAS PMID:19509286 A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP resul... | MODIFY | Summary: Mal described as a bridging adapter between TLR2/TLR4 and MyD88. Reason: Correct, but signaling adaptor activity is the more specific child term. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:19509286 It acts as a bridging adapter between the receptor and the sorting adapter MyD88 |
| GO:0030890 positive regulation of B cell proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tirap knockout data (PMID:12447442) showing loss of LPS-induced B cell proliferation. Reason: LPS-driven B cell proliferation is a downstream outcome of TLR4 signaling that requires TIRAP; this is a context-specific consequence rather than a core TIRAP function. Supporting Evidence: PMID:12447441 Here we report that LPS-induced splenocyte proliferation and cytokine production are abolished in mice lacking TIRAP. |
| GO:0031234 extrinsic component of cytoplasmic side of plasma membrane | IDA PMID:16751103 Phosphoinositide-mediated adaptor recruitment controls Toll-... | ACCEPT | Summary: TIRAP is recruited to the cytoplasmic face of the plasma membrane by its PIP2-binding domain. Reason: Precise description of TIRAP's core location. Supporting Evidence: PMID:16751103 We find that TIRAP contains a phosphatidylinositol 4,5-bisphosphate (PIP2) binding domain, which mediates TIRAP recruitment to the plasma membrane. |
| GO:0031334 positive regulation of protein-containing complex assembly | IDA PMID:12062447 Involvement of TIRAP/MAL in signaling for the activation of ... | UNDECIDED | Summary: Positive regulation of complex assembly attributed to a study of TIRAP in LPS-induced IRF3 activation. Reason: Only the abstract is cached; it reports TIRAP involvement in LPS-induced IRF3 activation but does not describe which complex assembly was measured. TIRAP does promote assembly of the TLR4-MyD88 complex (Kagan and Medzhitov), but it does so as a component of that complex rather than as a regulator. Cannot adjudicate without the full text. Supporting Evidence: PMID:12062447 Notably, our investigation revealed a critical function for TIRAP/MAL, a signaling adapter for Toll-like receptor (TLR) 4, in LPS-induced but not dsRNA-induced activation of IRF-3. PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. |
| GO:0032496 response to lipopolysaccharide | IDA PMID:11544529 Mal (MyD88-adapter-like) is required for Toll-like receptor-... | KEEP AS NON CORE | Summary: Mal is required for NF-kB activation in response to LPS via TLR4. Reason: Correct but general; toll-like receptor 4 signaling pathway is the more informative process term carried separately. Supporting Evidence: PMID:11544529 A dominant negative form of Mal inhibits NF-kappaB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-kappaB activation by IL-1RI or IL-18R. |
| GO:0032587 ruffle membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tirap localization (PMID:16751103) to PIP2-rich membrane ruffles. Reason: PIP2-rich plasma membrane subdomains such as ruffles are where TIRAP accumulates; a more specific plasma membrane location, acceptable but not core. Supporting Evidence: Reactome:R-HSA-2559456 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain |
| GO:0032648 regulation of interferon-beta production | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Transferred from mouse Tirap (source PMID:14630816). Reason: TIRAP-deficient or MyD88-binding-dead Mal macrophages induce IFN-beta normally after LPS, and TIRAP-deficient mice retain interferon-inducible gene expression; IFN-beta induction by TLR4 is TRIF/TRAM-dependent. Any TIRAP contribution is at most context-specific. Supporting Evidence: PMID:19509286 D96N expressing macrophages induced comparable amounts of IFN-Ξ² mRNA as WT and Mal-deficient cells. PMID:12447441 Expression of interferon-inducible genes and the maturation of dendritic cells is observed in these mice |
| GO:0032735 positive regulation of interleukin-12 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tirap knockout cytokine data (PMID:12447442). Reason: Cytokine production is a downstream output of TIRAP-dependent TLR2/TLR4 signaling. Supporting Evidence: PMID:12447441 Here we report that LPS-induced splenocyte proliferation and cytokine production are abolished in mice lacking TIRAP. |
| GO:0032738 positive regulation of interleukin-15 production | IDA PMID:18583567 Requirement of TLR2-mediated signaling for the induction of ... | KEEP AS NON CORE | Summary: siRNA knockdown of TIRAP reduced HSV-1/TLR2-induced IL-15 expression in THP1 cells. Reason: Downstream output of TLR2 signaling; valid but not core. Supporting Evidence: PMID:18583567 Interestingly, TIRAP/Mal, an adaptor molecule specifically recruited to TLR2 and TLR4, was also required for maximal up-regulation of IL-15. |
| GO:0032755 positive regulation of interleukin-6 production | IMP PMID:16301656 Toll-IL-1 receptor domain-containing adaptor protein is crit... | KEEP AS NON CORE | Summary: TIRAP blocking peptide abolished LPS-induced IL-6 in human alveolar macrophages. Reason: Downstream cytokine output of TIRAP-dependent TLR4 signaling. Supporting Evidence: PMID:16301656 The TIRAP blocking peptide abolished LPS-induced TNF-alpha, IL-6, and IL-8 expression in alveolar macrophages, whereas it attenuated E. coli-induced expression of these cytokines and chemokines. |
| GO:0032757 positive regulation of interleukin-8 production | IMP PMID:16301656 Toll-IL-1 receptor domain-containing adaptor protein is crit... | KEEP AS NON CORE | Summary: TIRAP blocking peptide abolished LPS-induced IL-8 in human alveolar macrophages. Reason: Downstream cytokine output of TIRAP-dependent TLR4 signaling. Supporting Evidence: PMID:16301656 The TIRAP blocking peptide abolished LPS-induced TNF-alpha, IL-6, and IL-8 expression in alveolar macrophages, whereas it attenuated E. coli-induced expression of these cytokines and chemokines. |
| GO:0032760 positive regulation of tumor necrosis factor production | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference of positive regulation of TNF production. Reason: Well supported downstream output of TIRAP-dependent signaling in human and mouse; non-core. Supporting Evidence: PMID:19509286 In Mal-deficient macrophages, TNFΞ± production in response to LPS was significantly reduced, whereas in response to PAM 2 CSK 4 , it was completely abrogated. |
| GO:0032760 positive regulation of tumor necrosis factor production | IMP PMID:16301656 Toll-IL-1 receptor domain-containing adaptor protein is crit... | KEEP AS NON CORE | Summary: TIRAP blocking peptide abolished LPS-induced TNF-alpha in human alveolar macrophages. Reason: Downstream cytokine output. Supporting Evidence: PMID:16301656 The TIRAP blocking peptide abolished LPS-induced TNF-alpha, IL-6, and IL-8 expression in alveolar macrophages, whereas it attenuated E. coli-induced expression of these cytokines and chemokines. |
| GO:0032760 positive regulation of tumor necrosis factor production | IMP PMID:19509286 A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP resul... | KEEP AS NON CORE | Summary: Mal-deficient macrophages have reduced LPS- and abolished PAM2CSK4-induced TNF production. Reason: Downstream cytokine output. Supporting Evidence: PMID:19509286 In Mal-deficient macrophages, TNFΞ± production in response to LPS was significantly reduced, whereas in response to PAM 2 CSK 4 , it was completely abrogated. |
| GO:0034137 positive regulation of toll-like receptor 2 signaling pathway | IMP PMID:19509286 A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP resul... | MODIFY | Summary: Mal is required for TLR2 (PAM2CSK4) signaling to NF-kB and TNF. Reason: TIRAP is a component of the TLR2 signaling pathway (it bridges TLR2 to MyD88), not an external regulator of it. The pathway membership term is appropriate. Proposed replacements: toll-like receptor 2 signaling pathway Supporting Evidence: PMID:19509286 In Mal-deficient macrophages, IΞΊB degradation is abrogated upon PAM 2 CSK 4 treatment, whereas for LPS stimulation Mal-deficient macrophages undergo delayed degradation PMID:19509286 It acts as a bridging adapter between the receptor and the sorting adapter MyD88 |
| GO:0034141 positive regulation of toll-like receptor 3 signaling pathway | ISS GO_REF:0000024 | REMOVE | Summary: Transferred from a mouse Tirap annotation. Reason: Contradicted: TIRAP-deficient mice respond normally to TLR3 ligands, and TLR3 (poly I:C) signaling is Mal-independent in reconstituted macrophages. TLR3 signals through TRIF, not the TIRAP-MyD88 axis. Supporting Evidence: PMID:12447441 they also show defective response to TLR2 ligands, but not to stimuli that activate TLR3, TLR7 or TLR9. PMID:19509286 Poly(IΒ·C) is a TLR3 ligand whose signaling is independent of Mal |
| GO:0034142 toll-like receptor 4 signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that TIRAP family members act in TLR4 signaling. Reason: Core process, supported by extensive human and mouse experimental data. Supporting Evidence: PMID:11544529 Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction. PMID:12447441 Instead, TIRAP has a crucial role in the MyD88-dependent signalling pathway shared by TLR2 and TLR4. |
| GO:0034142 toll-like receptor 4 signaling pathway | IDA PMID:16751103 Phosphoinositide-mediated adaptor recruitment controls Toll-... | ACCEPT | Summary: TIRAP facilitates MyD88 delivery to activated TLR4 to initiate signaling. Reason: Core process. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. |
| GO:0034145 positive regulation of toll-like receptor 4 signaling pathway | IMP PMID:19509286 A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP resul... | MODIFY | Summary: Mal is required for the MyD88 branch of TLR4 signaling. Reason: TIRAP is a component of the TLR4 pathway rather than a regulator of it; the specific pathway term TIRAP-dependent toll-like receptor 4 signaling pathway is appropriate. Proposed replacements: TIRAP-dependent toll-like receptor 4 signaling pathway Supporting Evidence: PMID:19509286 In Mal-deficient macrophages, IΞΊB degradation is abrogated upon PAM 2 CSK 4 treatment, whereas for LPS stimulation Mal-deficient macrophages undergo delayed degradation PMID:19509286 It acts as a bridging adapter between the receptor and the sorting adapter MyD88 |
| GO:0035591 signaling adaptor activity | IDA PMID:16751103 Phosphoinositide-mediated adaptor recruitment controls Toll-... | ACCEPT | Summary: TIRAP binds PIP2 and activated TLR4 and recruits MyD88 to the receptor. Reason: Core MF: TIRAP is a bridging (sorting) signaling 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:0035662 Toll-like receptor 4 binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of TLR4 binding. Reason: Supported by direct experimental data in human. Supporting Evidence: PMID:11544529 Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction. |
| GO:0035662 Toll-like receptor 4 binding | IPI PMID:19509286 A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP resul... | ACCEPT | Summary: Mal co-immunoprecipitates with TLR4; D96N retains TLR4 binding. Reason: Core receptor-binding activity. Supporting Evidence: PMID:19509286 As expected, wild type Mal interacted with the receptors TLR2 ( Fig. 4 A ) and TLR4 ( Fig. 4 B ) and with MyD88 ( Fig. 4 C , lane 6 ). |
| GO:0035663 Toll-like receptor 2 binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of TLR2 binding. Reason: Supported by direct experimental data in human. Supporting Evidence: PMID:17322885 As shown in Fig. 5 upper panel, a GST-tagged version of the TIRAP 180-Leu containing allotype, unlike wild-type TIRAP, failed to bind to TLR2 |
| GO:0035663 Toll-like receptor 2 binding | IPI PMID:19509286 A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP resul... | ACCEPT | Summary: Mal co-immunoprecipitates with TLR2. Reason: Core receptor-binding activity. Supporting Evidence: PMID:19509286 As expected, wild type Mal interacted with the receptors TLR2 ( Fig. 4 A ) and TLR4 ( Fig. 4 B ) and with MyD88 ( Fig. 4 C , lane 6 ). |
| GO:0035665 TIRAP-dependent toll-like receptor 4 signaling pathway | IDA PMID:11544529 Mal (MyD88-adapter-like) is required for Toll-like receptor-... | ACCEPT | Summary: Mal is an adapter in TLR4 signal transduction; dominant-negative Mal blocks TLR4-induced NF-kB. Reason: Core process; the term is defined around TIRAP itself. Supporting Evidence: PMID:11544529 Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction. PMID:11544529 A dominant negative form of Mal inhibits NF-kappaB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-kappaB activation by IL-1RI or IL-18R. |
| GO:0038123 toll-like receptor TLR1:TLR2 signaling pathway | IDA PMID:17322885 A Mal functional variant is associated with protection again... | MODIFY | Summary: TIRAP reconstitution of TLR2 signaling in Tirap-deficient cells. Reason: The paper's TLR2 experiments used Malp2, a diacylated lipopeptide described only as a TLR2 ligand; it does not test the TLR1:TLR2 heterodimer specifically (diacyl lipopeptides act through TLR2:TLR6). The generic toll-like receptor 2 signaling pathway term matches what was shown. Proposed replacements: toll-like receptor 2 signaling pathway Supporting Evidence: PMID:17322885 Treatment of wild type MEFs with the TLR2 ligand Malp2 induced I-ΞΊBΞ± degradation at 30 and 50 minutes (first panel). This effect was absent in Tirap-deficient MEFs (second panel). |
| GO:0042802 identical protein binding | IPI PMID:17258210 MAPPIT analysis of TLR adaptor complexes. | KEEP AS NON CORE | Summary: MAPPIT detected Mal homodimerization. Reason: Homotypic TIR-TIR association is part of the signaling mechanism but not the defining function. 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 provides an initial mechanistic insight in this bridging function of Mal. |
| GO:0042802 identical protein binding | IPI PMID:21873236 Crystal structure of Toll-like receptor adaptor MAL/TIRAP re... | KEEP AS NON CORE | Summary: Crystal structure revealed dimerization interfaces confirmed by mutagenesis. Reason: Mechanistic detail of the adaptor; non-core. 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. PMID:21873236 Although purified MAL behaves as a monomer in solution, it forms a homodimer in vivo |
| GO:0042802 identical protein binding | IPI PMID:24275656 Crystal structures of the Toll/Interleukin-1 receptor (TIR) ... | KEEP AS NON CORE | Summary: TIRAP TIR domain dimer observed in the crystal structure. Reason: Mechanistic detail; non-core. Supporting Evidence: PMID:24275656 the TIRAP TIR domain dimer mediated by its Ξ±Cβ² and Ξ±D helices |
| GO:0042802 identical protein binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tirap self-association. Reason: Consistent with human data; non-core. Supporting Evidence: PMID:11544529 Mal can form homodimers and can also form heterodimers with MyD88. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of positive regulation of canonical NF-kB signaling. Reason: TIRAP-dependent TLR2/TLR4 signaling activates canonical NF-kB; well supported. Supporting Evidence: PMID:19509286 In Mal-deficient macrophages, IΞΊB degradation is abrogated upon PAM 2 CSK 4 treatment, whereas for LPS stimulation Mal-deficient macrophages undergo delayed degradation |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IMP PMID:19509286 A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP resul... | ACCEPT | Summary: Mal-deficient macrophages fail to degrade IkB after PAM2CSK4 and show delayed degradation after LPS. Reason: Direct experimental support. Supporting Evidence: PMID:19509286 In Mal-deficient macrophages, IΞΊB degradation is abrogated upon PAM 2 CSK 4 treatment, whereas for LPS stimulation Mal-deficient macrophages undergo delayed degradation |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IMP PMID:24275656 Crystal structures of the Toll/Interleukin-1 receptor (TIR) ... | ACCEPT | Summary: TIRAP-driven NF-kB reporter activity, inhibited by Brucella TcpB. Reason: Consistent with TIRAP's established role upstream of NF-kB activation. Supporting Evidence: PMID:24275656 heterotypic TcpB and TIRAP interaction by co-immunoprecipitation and NF-ΞΊB reporter assays |
| GO:0045088 regulation of innate immune response | IC PMID:19509286 A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP resul... | KEEP AS NON CORE | Summary: Inferred from TIRAP's role in TLR4 signaling. Reason: True but vague; the specific TLR pathway terms are more informative. Supporting Evidence: PMID:19509286 The adapter protein Mal/TIRAP (hereafter referred to as Mal) is involved in the MyD88-dependent pathway downstream of TLR2 and TLR4 |
| GO:0046330 positive regulation of JNK cascade | IMP PMID:11544529 Mal (MyD88-adapter-like) is required for Toll-like receptor-... | KEEP AS NON CORE | Summary: Mal activates JNK. Reason: Downstream output of TIRAP-MyD88 signaling; valid but non-core. Supporting Evidence: PMID:11544529 Mal activates NF-kappaB, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. |
| GO:0050830 defense response to Gram-positive bacterium | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tirap infection phenotype (PMID:15690042). Reason: TIRAP-dependent TLR2 signaling contributes to host defense against Gram-positive bacteria; human genetic association data (S180L) also link TIRAP to bacterial disease outcomes. Non-core. Supporting Evidence: PMID:17322885 We found that the Mal S180L variant attenuated TLR2 signal transduction. |
| GO:0060090 molecular adaptor activity | IDA PMID:11544529 Mal (MyD88-adapter-like) is required for Toll-like receptor-... | MODIFY | Summary: Mal acts as an adapter in TLR4 signal transduction. Reason: Correct but general; signaling adaptor activity is the precise term. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:11544529 Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction. |
| GO:0060090 molecular adaptor activity | IDA PMID:16751103 Phosphoinositide-mediated adaptor recruitment controls Toll-... | MODIFY | Summary: TIRAP functions to deliver MyD88 to activated TLR4. Reason: Correct but general; signaling adaptor activity (already annotated from this paper) is the precise term. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IMP PMID:11544529 Mal (MyD88-adapter-like) is required for Toll-like receptor-... | KEEP AS NON CORE | Summary: Mal activates ERK1/2. Reason: Downstream output; non-core. Supporting Evidence: PMID:11544529 Mal activates NF-kappaB, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. |
| GO:0070935 3'-UTR-mediated mRNA stabilization | IDA PMID:15294994 Toll IL-1 receptors differ in their ability to promote the s... | MARK AS OVER ANNOTATED | Summary: Overexpression of Mal promoted stabilization of ARE-containing chemokine mRNA in HEK293 cells. Reason: TIRAP does not act on mRNA; stabilization is a distal consequence of MyD88-dependent kinase signaling. The gene product does none of the work of 3'-UTR-mediated mRNA stabilization. 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:0071221 cellular response to bacterial lipopeptide | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tirap knockout responses to bacterial lipopeptides (PMID:15690042). Reason: Correct: lipopeptide responses via TLR2 require TIRAP; covered more precisely by the TLR2 pathway. Supporting Evidence: PMID:17322885 Treatment of wild type MEFs with the TLR2 ligand Malp2 induced I-ΞΊBΞ± degradation at 30 and 50 minutes (first panel). This effect was absent in Tirap-deficient MEFs (second panel). |
| GO:0071223 cellular response to lipoteichoic acid | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tirap knockout responses to lipoteichoic acid (PMID:15690042). Reason: Plausible TLR2-mediated response; non-core. Supporting Evidence: PMID:12447441 Instead, TIRAP has a crucial role in the MyD88-dependent signalling pathway shared by TLR2 and TLR4. |
| GO:0090023 positive regulation of neutrophil chemotaxis | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Transferred from mouse Tirap data (PMID:18039275) on neutrophil recruitment. Reason: Neutrophil recruitment in Tirap-deficient lungs is lost because chemokine production (KC, MIP-2) is lost; TIRAP acts in the upstream TLR signaling cell, not in neutrophil chemotaxis itself. Supporting Evidence: PMID:16301656 LPS-induced neutrophil sequestration; NF-kappaB translocation; keratinocyte cell-derived chemokine, MIP-2, TNF-alpha, and IL-6 expression; histopathology; and VCAM-1 and ICAM-1 expression were abolished in the lungs of TIRAP-/- mice. |
| GO:2000340 positive regulation of chemokine (C-X-C motif) ligand 1 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tirap knockout (KC/CXCL1 loss in lung). Reason: Downstream chemokine output; non-core. Supporting Evidence: PMID:16301656 LPS-induced neutrophil sequestration; NF-kappaB translocation; keratinocyte cell-derived chemokine, MIP-2, TNF-alpha, and IL-6 expression; histopathology; and VCAM-1 and ICAM-1 expression were abolished in the lungs of TIRAP-/- mice. |
| GO:2000343 positive regulation of chemokine (C-X-C motif) ligand 2 production | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference of positive regulation of CXCL2 production. Reason: Downstream chemokine output (MIP-2 in mouse lung); non-core. Supporting Evidence: PMID:16301656 LPS-induced neutrophil sequestration; NF-kappaB translocation; keratinocyte cell-derived chemokine, MIP-2, TNF-alpha, and IL-6 expression; histopathology; and VCAM-1 and ICAM-1 expression were abolished in the lungs of TIRAP-/- mice. |
| GO:2000343 positive regulation of chemokine (C-X-C motif) ligand 2 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tirap knockout (MIP-2/CXCL2 loss in lung). Reason: Downstream chemokine output; non-core. Supporting Evidence: PMID:16301656 LPS-induced neutrophil sequestration; NF-kappaB translocation; keratinocyte cell-derived chemokine, MIP-2, TNF-alpha, and IL-6 expression; histopathology; and VCAM-1 and ICAM-1 expression were abolished in the lungs of TIRAP-/- mice. |
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Download this section (compressed HTML)Q: Beyond TLR2 and TLR4 at the plasma membrane, does TIRAP act as a bridging adaptor for endosomal TLRs (e.g. TLR9) in human cells, and if so through which endosomal phosphoinositide?
Q: Is TIRAP a physiological adaptor for RAGE signaling in vivo, and should RAGE-dependent signaling be represented as a TIRAP process (no specific GO pathway term currently exists)?
Q: What is the mechanistic basis for the disputed disease associations of the S180L variant, given reports that it abolishes TLR2 binding versus population studies that fail to replicate?
Q: Should 'positive regulation of toll-like receptor N signaling pathway' annotations on obligate pathway components such as TIRAP be systematically converted to pathway membership terms?
Experiment: CRISPR knockout of TIRAP in human primary macrophages or iPSC-derived macrophages, profiling responses to TLR1/2, TLR2/6, TLR4, TLR7/8 and TLR9 agonists across a ligand dose range, to define human TLR adaptor requirements.
Experiment: Reconstitution of TIRAP-null human cells with PIP2-binding motif mutants and membrane-targeting chimeras to test whether membrane targeting alone accounts for TIRAP's requirement.
Experiment: In vitro reconstitution of TLR4-TIR / TIRAP / MyD88 complex assembly with S180L and D96N variants, measured by cryo-EM or fluorescence polarization, to quantify variant effects on nucleation.
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