TOLLIP encodes Toll-interacting protein, a non-enzymatic ubiquitin/phosphoinositide-binding adaptor that links endosomal membranes, TOM1/clathrin-associated trafficking, and TLR/IL-1 receptor signaling. Its core roles are CUE-domain ubiquitin recognition, C2-domain membrane/endosome targeting, PI3P-dependent endolysosomal routing of ubiquitinated or aberrant cargo, and regulated restraint of IRAK-dependent innate immune signaling.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Cytoplasm is the broad cellular compartment for TOLLIP adaptor activity and endosomal trafficking. Reason: cytoplasm is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0006511 ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Ubiquitin-dependent protein catabolic process is supported by TOLLIP-mediated routing of ubiquitinated or aberrant cargo to endolysosomal degradation. Reason: ubiquitin-dependent protein catabolic process is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **Endosomal/lysosomal trafficking and protein quality control**: TOLLIP functions as a cargo adaptor linking aberrant/ubiquitinated membrane proteins to PI3P-dependent lysosomal routing and degradation, operating alongside ERAD |
| GO:0031624 ubiquitin conjugating enzyme binding | IBA GO_REF:0000033 | MODIFY | Summary: The evidence supports CUE-domain recognition of ubiquitin conjugates rather than a specific ubiquitin-conjugating enzyme binding function. Reason: ubiquitin conjugating enzyme binding is less precise than the supported TOLLIP mechanism. Proposed replacements: ubiquitin binding Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0043130 ubiquitin binding | IBA GO_REF:0000033 | ACCEPT | Summary: Ubiquitin binding is a core CUE-domain molecular function of TOLLIP. Reason: ubiquitin binding is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** |
| GO:0002376 immune system process | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: immune system process is plausible as a context-specific or secondary TOLLIP-associated annotation, but it is not the most precise core function. Reason: immune system process is secondary to TOLLIP ubiquitin/membrane adaptor and TLR/IL-1R signaling roles. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **TLR/ILβ1R β Myddosome/IRAK1 β NFβΞΊB**: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NFβΞΊB signaling |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasm is the broad cellular compartment for TOLLIP adaptor activity and endosomal trafficking. Reason: cytoplasm is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0005768 endosome | IEA GO_REF:0000044 | ACCEPT | Summary: Endosome localization is central to TOLLIP PI3P-dependent cargo routing. Reason: endosome is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo file:human/TOLLIP/TOLLIP-deep-research-falcon.md **Endosomal/lysosomal trafficking and protein quality control**: TOLLIP functions as a cargo adaptor linking aberrant/ubiquitinated membrane proteins to PI3P-dependent lysosomal routing and degradation, operating alongside ERAD |
| GO:0005769 early endosome | IEA GO_REF:0000044 | ACCEPT | Summary: Early endosome localization is supported by TOLLIP coupling of PI3P vesicles to cargo trafficking. Reason: early endosome is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo file:human/TOLLIP/TOLLIP-deep-research-falcon.md **Endosomal/lysosomal trafficking and protein quality control**: TOLLIP functions as a cargo adaptor linking aberrant/ubiquitinated membrane proteins to PI3P-dependent lysosomal routing and degradation, operating alongside ERAD |
| GO:0006914 autophagy | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: autophagy is plausible as a context-specific or secondary TOLLIP-associated annotation, but it is not the most precise core function. Reason: autophagy is secondary to TOLLIP ubiquitin/membrane adaptor and TLR/IL-1R signaling roles. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo file:human/TOLLIP/TOLLIP-deep-research-falcon.md **Endosomal/lysosomal trafficking and protein quality control**: TOLLIP functions as a cargo adaptor linking aberrant/ubiquitinated membrane proteins to PI3P-dependent lysosomal routing and degradation, operating alongside ERAD |
| GO:0006954 inflammatory response | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: inflammatory response is plausible as a context-specific or secondary TOLLIP-associated annotation, but it is not the most precise core function. Reason: inflammatory response is secondary to TOLLIP ubiquitin/membrane adaptor and TLR/IL-1R signaling roles. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **TLR/ILβ1R β Myddosome/IRAK1 β NFβΞΊB**: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NFβΞΊB signaling |
| GO:0043130 ubiquitin binding | IEA GO_REF:0000002 | ACCEPT | Summary: Ubiquitin binding is a core CUE-domain molecular function of TOLLIP. Reason: ubiquitin binding is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** |
| GO:0045087 innate immune response | IEA GO_REF:0000043 | ACCEPT | Summary: Innate immune response is supported through TOLLIP regulation of TLR/IL-1R signaling outputs. Reason: innate immune response is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **TLR/ILβ1R β Myddosome/IRAK1 β NFβΞΊB**: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NFβΞΊB signaling |
| GO:0005515 protein binding | IPI PMID:14563850 Tom1, a VHS domain-containing protein, interacts with tollip... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:16713569 A protein-protein interaction network for human inherited at... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:19060904 An empirical framework for binary interactome mapping. | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:19447967 Shifted Transversal Design smart-pooling for high coverage i... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:20936779 A human MAP kinase interactome. | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:25042851 Autophagic clearance of polyQ proteins mediated by ubiquitin... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:27107014 An inter-species protein-protein interaction network across ... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:34524948 Global Proximity Interactome of the Human Macroautophagy Pat... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005150 interleukin-1, type I receptor binding | IEA GO_REF:0000107 | ACCEPT | Summary: Interleukin-1 type I receptor binding is supported as part of the IL-1R/TLR signaling adaptor-regulator role. Reason: interleukin-1, type I receptor binding is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md **TLR/ILβ1R β Myddosome/IRAK1 β NFβΞΊB**: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NFβΞΊB signaling |
| GO:0016604 nuclear body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: nuclear body is plausible as a context-specific or secondary TOLLIP-associated annotation, but it is not the most precise core function. Reason: nuclear body is secondary to TOLLIP ubiquitin/membrane adaptor and TLR/IL-1R signaling roles. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo file:human/TOLLIP/TOLLIP-deep-research-falcon.md **Endosomal/lysosomal trafficking and protein quality control**: TOLLIP functions as a cargo adaptor linking aberrant/ubiquitinated membrane proteins to PI3P-dependent lysosomal routing and degradation, operating alongside ERAD |
| GO:0031624 ubiquitin conjugating enzyme binding | IEA GO_REF:0000107 | MODIFY | Summary: The evidence supports CUE-domain recognition of ubiquitin conjugates rather than a specific ubiquitin-conjugating enzyme binding function. Reason: ubiquitin conjugating enzyme binding is less precise than the supported TOLLIP mechanism. Proposed replacements: ubiquitin binding Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0031625 ubiquitin protein ligase binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ubiquitin protein ligase binding is not the main supported activity; the reviewed evidence emphasizes ubiquitin conjugate binding and adaptor function. Reason: ubiquitin protein ligase binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0032183 SUMO binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: SUMO binding is not supported by the Falcon synthesis as a core or well-grounded TOLLIP function. Reason: SUMO binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | ACCEPT | Summary: Protein-containing complex is supported because TOLLIP acts in TOM1/clathrin, cargo, IRAK, and receptor-proximal complexes. Reason: protein-containing complex is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **TLR/ILβ1R β Myddosome/IRAK1 β NFβΞΊB**: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NFβΞΊB signaling |
| GO:0033235 positive regulation of protein sumoylation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Positive regulation of protein sumoylation is not supported as a TOLLIP core function in the reviewed evidence. Reason: positive regulation of protein sumoylation overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: perinuclear region of cytoplasm is plausible as a context-specific or secondary TOLLIP-associated annotation, but it is not the most precise core function. Reason: perinuclear region of cytoplasm is secondary to TOLLIP ubiquitin/membrane adaptor and TLR/IL-1R signaling roles. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo file:human/TOLLIP/TOLLIP-deep-research-falcon.md **Endosomal/lysosomal trafficking and protein quality control**: TOLLIP functions as a cargo adaptor linking aberrant/ubiquitinated membrane proteins to PI3P-dependent lysosomal routing and degradation, operating alongside ERAD |
| GO:0070498 interleukin-1-mediated signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Interleukin-1-mediated signaling pathway is a supported core immune-signaling context for TOLLIP. Reason: interleukin-1-mediated signaling pathway is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md **TLR/ILβ1R β Myddosome/IRAK1 β NFβΞΊB**: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NFβΞΊB signaling |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal and receptor-signaling compartments. Reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0005515 protein binding | IPI PMID:26320582 Tom1 Modulates Binding of Tollip to Phosphatidylinositol 3-P... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:31263572 Dominant TOM1 mutation associated with combined immunodefici... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005515 protein binding | IPI PMID:15047686 Tollip and Tom1 form a complex and recruit ubiquitin-conjuga... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0019897 extrinsic component of plasma membrane | IC PMID:10854325 Tollip, a new component of the IL-1RI pathway, links IRAK to... | KEEP AS NON CORE | Summary: extrinsic component of plasma membrane is plausible as a context-specific or secondary TOLLIP-associated annotation, but it is not the most precise core function. Reason: extrinsic component of plasma membrane is secondary to TOLLIP ubiquitin/membrane adaptor and TLR/IL-1R signaling roles. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo file:human/TOLLIP/TOLLIP-deep-research-falcon.md **Endosomal/lysosomal trafficking and protein quality control**: TOLLIP functions as a cargo adaptor linking aberrant/ubiquitinated membrane proteins to PI3P-dependent lysosomal routing and degradation, operating alongside ERAD |
| GO:0060090 molecular adaptor activity | IDA PMID:10854325 Tollip, a new component of the IL-1RI pathway, links IRAK to... | ACCEPT | Summary: Molecular adaptor activity captures the core TOLLIP role in linking cargo, endosomal membranes, and receptor-signaling proteins. Reason: molecular adaptor activity is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **Endosomal/lysosomal trafficking and protein quality control**: TOLLIP functions as a cargo adaptor linking aberrant/ubiquitinated membrane proteins to PI3P-dependent lysosomal routing and degradation, operating alongside ERAD |
| GO:0070498 interleukin-1-mediated signaling pathway | IDA PMID:10854325 Tollip, a new component of the IL-1RI pathway, links IRAK to... | ACCEPT | Summary: Interleukin-1-mediated signaling pathway is a supported core immune-signaling context for TOLLIP. Reason: interleukin-1-mediated signaling pathway is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md **TLR/ILβ1R β Myddosome/IRAK1 β NFβΞΊB**: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NFβΞΊB signaling |
| GO:0060090 molecular adaptor activity | IDA PMID:27368102 An ER-Associated Pathway Defines Endosomal Architecture for ... | ACCEPT | Summary: Molecular adaptor activity captures the core TOLLIP role in linking cargo, endosomal membranes, and receptor-signaling proteins. Reason: molecular adaptor activity is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **Endosomal/lysosomal trafficking and protein quality control**: TOLLIP functions as a cargo adaptor linking aberrant/ubiquitinated membrane proteins to PI3P-dependent lysosomal routing and degradation, operating alongside ERAD |
| GO:0019900 kinase binding | IPI PMID:10854325 Tollip, a new component of the IL-1RI pathway, links IRAK to... | ACCEPT | Summary: Kinase binding is supported by TOLLIP interactions with IRAK1 and BLK in receptor-proximal signaling control. Reason: kinase binding is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md **TLR/ILβ1R β Myddosome/IRAK1 β NFβΞΊB**: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NFβΞΊB signaling file:human/TOLLIP/TOLLIP-deep-research-falcon.md BLK binding and phosphorylation promote **dissociation of TOLLIP from IRAK1**, exposing IRAK1 phosphorylation sites (ProST region) and enabling **IRAK1 hyperphosphorylation**, downstream **NFβΞΊB activation**, and inflammatory cytokine responses |
| GO:0032991 protein-containing complex | IDA PMID:10854325 Tollip, a new component of the IL-1RI pathway, links IRAK to... | ACCEPT | Summary: Protein-containing complex is supported because TOLLIP acts in TOM1/clathrin, cargo, IRAK, and receptor-proximal complexes. Reason: protein-containing complex is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **TLR/ILβ1R β Myddosome/IRAK1 β NFβΞΊB**: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NFβΞΊB signaling |
| GO:0005515 protein binding | IPI PMID:11397809 IRAK1b, a novel alternative splice variant of interleukin-1 ... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798749 | MARK AS OVER ANNOTATED | Summary: Extracellular region is inconsistent with the reviewed intracellular adaptor/endosomal functions of TOLLIP. Reason: extracellular region overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798751 | MARK AS OVER ANNOTATED | Summary: Extracellular region is inconsistent with the reviewed intracellular adaptor/endosomal functions of TOLLIP. Reason: extracellular region overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0035578 azurophil granule lumen | TAS Reactome:R-HSA-6798751 | MARK AS OVER ANNOTATED | Summary: Azurophil granule lumen is a context-specific secretory-granule annotation and is not supported as a functional TOLLIP location. Reason: azurophil granule lumen overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0035580 specific granule lumen | TAS Reactome:R-HSA-6798749 | MARK AS OVER ANNOTATED | Summary: Specific granule lumen is a context-specific secretory-granule annotation and is not supported as a functional TOLLIP location. Reason: specific granule lumen overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | MARK AS OVER ANNOTATED | Summary: Extracellular exosome detection does not represent the core intracellular adaptor function of TOLLIP. Reason: extracellular exosome overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0030855 epithelial cell differentiation | IEP PMID:21492153 Analysis of proteomic changes induced upon cellular differen... | KEEP AS NON CORE | Summary: epithelial cell differentiation is plausible as a context-specific or secondary TOLLIP-associated annotation, but it is not the most precise core function. Reason: epithelial cell differentiation is secondary to TOLLIP ubiquitin/membrane adaptor and TLR/IL-1R signaling roles. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo file:human/TOLLIP/TOLLIP-deep-research-falcon.md **Endosomal/lysosomal trafficking and protein quality control**: TOLLIP functions as a cargo adaptor linking aberrant/ubiquitinated membrane proteins to PI3P-dependent lysosomal routing and degradation, operating alongside ERAD |
| GO:0005515 protein binding | IPI PMID:16412388 Recruitment of clathrin onto endosomes by the Tom1-Tollip co... | MARK AS OVER ANNOTATED | Summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding, receptor-binding, and kinase-binding terms better capture the mechanism. Reason: protein binding overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **CUE domain (C-terminal; mapped as aa 231β274)**: mediates **ubiquitin conjugate binding** and is also implicated in receptor-proximal innate immune pathway interactions (e.g., IRAK and receptor TIR domains in review synthesis) |
| GO:0036010 protein localization to endosome | IDA PMID:16412388 Recruitment of clathrin onto endosomes by the Tom1-Tollip co... | ACCEPT | Summary: Protein localization to endosome is supported by the TOLLIP cargo-routing mechanism. Reason: protein localization to endosome is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md **Endosomal/lysosomal trafficking and protein quality control**: TOLLIP functions as a cargo adaptor linking aberrant/ubiquitinated membrane proteins to PI3P-dependent lysosomal routing and degradation, operating alongside ERAD file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: Extracellular exosome detection does not represent the core intracellular adaptor function of TOLLIP. Reason: extracellular exosome overstates or obscures the supported TOLLIP function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446634 | ACCEPT | Summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal and receptor-signaling compartments. Reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446684 | ACCEPT | Summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal and receptor-signaling compartments. Reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446692 | ACCEPT | Summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal and receptor-signaling compartments. Reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446694 | ACCEPT | Summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal and receptor-signaling compartments. Reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446701 | ACCEPT | Summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal and receptor-signaling compartments. Reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446862 | ACCEPT | Summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal and receptor-signaling compartments. Reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446868 | ACCEPT | Summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal and receptor-signaling compartments. Reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446894 | ACCEPT | Summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal and receptor-signaling compartments. Reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0005737 cytoplasm | IC PMID:11441107 Cooperation of Toll-like receptor 2 and 6 for cellular activ... | ACCEPT | Summary: Cytoplasm is the broad cellular compartment for TOLLIP adaptor activity and endosomal trafficking. Reason: cytoplasm is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIPβs C2 domain supports association with **PI3P-enriched membranes/vesicles** and **endosomal/lysosomal compartments**, aligning with its roles in endosomal sorting and lysosomal delivery of cargo |
| GO:0007165 signal transduction | IPI PMID:11441107 Cooperation of Toll-like receptor 2 and 6 for cellular activ... | MODIFY | Summary: Generic signal transduction should be refined to the IL-1R/TLR receptor signaling context supported for TOLLIP. Reason: signal transduction is less precise than the supported TOLLIP mechanism. Proposed replacements: interleukin-1-mediated signaling pathway Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md **TLR/ILβ1R β Myddosome/IRAK1 β NFβΞΊB**: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NFβΞΊB signaling |
| GO:0035325 Toll-like receptor binding | IPI PMID:11441107 Cooperation of Toll-like receptor 2 and 6 for cellular activ... | ACCEPT | Summary: Toll-like receptor binding is supported as part of TOLLIP receptor-proximal innate immune signaling regulation. Reason: Toll-like receptor binding is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate immune signaling function. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **TLR/ILβ1R β Myddosome/IRAK1 β NFβΞΊB**: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NFβΞΊB signaling |
| GO:0016310 phosphorylation | IDA PMID:1085432 Malignant lymphoma and rheumatic symptoms. | REMOVE | Summary: TOLLIP is phosphorylated by BLK during signaling, but TOLLIP is not a kinase and should not be annotated to phosphorylation as an activity/process it performs. Reason: TOLLIP is a phosphorylation-regulated adaptor, not an enzyme that catalyzes phosphorylation. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md BLK binding and phosphorylation promote **dissociation of TOLLIP from IRAK1**, exposing IRAK1 phosphorylation sites (ProST region) and enabling **IRAK1 hyperphosphorylation**, downstream **NFβΞΊB activation**, and inflammatory cytokine responses |
| GO:0045321 leukocyte activation | NAS PMID:11441107 Cooperation of Toll-like receptor 2 and 6 for cellular activ... | KEEP AS NON CORE | Summary: leukocyte activation is plausible as a context-specific or secondary TOLLIP-associated annotation, but it is not the most precise core function. Reason: leukocyte activation is secondary to TOLLIP ubiquitin/membrane adaptor and TLR/IL-1R signaling roles. Supporting Evidence: file:human/TOLLIP/TOLLIP-deep-research-falcon.md TOLLIP is best understood as a **multifunctional adaptor/regulator** that couples **ubiquitin recognition** and **membrane/endosomal phosphoinositide recognition** to (i) **tuning innate immune receptor signaling** (TLR/ILβ1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation** file:human/TOLLIP/TOLLIP-deep-research-falcon.md **TLR/ILβ1R β Myddosome/IRAK1 β NFβΞΊB**: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NFβΞΊB signaling |
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