TOLLIP

Existing Annotations Review

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 TOLLIP’s 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/IL‑1R 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 231–274): 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 231–274): 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/IL‑1R 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/IL‑1R pathways) and (ii) sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation file:human/TOLLIP/TOLLIP-deep-research-falcon.md TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NF‑κB 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 TOLLIP’s 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 TOLLIP’s 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 TOLLIP’s 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 TOLLIP’s 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/IL‑1R pathways) and (ii) sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation file:human/TOLLIP/TOLLIP-deep-research-falcon.md TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NF‑κB 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 231–274): 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/IL‑1R 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/IL‑1R pathways) and (ii) sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation file:human/TOLLIP/TOLLIP-deep-research-falcon.md TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NF‑κB 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R → Myddosome/IRAK1 → NF‑κB: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NF‑κB 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 TOLLIP’s 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 231–274): 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 231–274): 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/IL‑1R 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/IL‑1R pathways) and (ii) sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation file:human/TOLLIP/TOLLIP-deep-research-falcon.md TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NF‑κB 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/IL‑1R 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 TOLLIP’s 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/IL‑1R → Myddosome/IRAK1 → NF‑κB: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NF‑κB 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 TOLLIP’s 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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/IL‑1R 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 231–274): 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 TOLLIP’s 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/IL‑1R 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/IL‑1R → Myddosome/IRAK1 → NF‑κB: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NF‑κB 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/IL‑1R 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/IL‑1R → Myddosome/IRAK1 → NF‑κB: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NF‑κB 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 NF‑κB 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/IL‑1R pathways) and (ii) sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation file:human/TOLLIP/TOLLIP-deep-research-falcon.md TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NF‑κB 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/IL‑1R 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 231–274): 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 TOLLIP’s 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 TOLLIP’s 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 TOLLIP’s 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 TOLLIP’s 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 TOLLIP’s 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 TOLLIP’s 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/IL‑1R 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 231–274): 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 TOLLIP’s 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 TOLLIP’s 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 TOLLIP’s 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 TOLLIP’s 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 TOLLIP’s 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 TOLLIP’s 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 TOLLIP’s 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 TOLLIP’s 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 TOLLIP’s 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 TOLLIP’s 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 TOLLIP’s 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/IL‑1R → Myddosome/IRAK1 → NF‑κB: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NF‑κB 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/IL‑1R pathways) and (ii) sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation file:human/TOLLIP/TOLLIP-deep-research-falcon.md TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NF‑κB 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 NF‑κB 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/IL‑1R pathways) and (ii) sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation file:human/TOLLIP/TOLLIP-deep-research-falcon.md TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NF‑κB signaling

Core Functions

Ubiquitin- and phosphoinositide-directed molecular adaptor activity that routes ubiquitinated or aberrant membrane cargo toward endolysosomal degradation.

Molecular Function:

molecular adaptor activity

Directly Involved In:

protein localization to endosome ubiquitin-dependent protein catabolic process

Cellular Locations:

endosome early endosome cytoplasm

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/IL‑1R pathways) and (ii) **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation**
file:human/TOLLIP/TOLLIP-deep-research-falcon.md
**C2 domain (~central ~130 aa)**: binds **phosphoinositides**; in a 2023 mechanistic study, the C2 domain showed preferential interaction with **PI3P** and **PI(4,5)P2**, consistent with **membrane/endosome targeting** and PI3P-vesicle coupling
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

CUE-domain ubiquitin-conjugate binding that supports cargo selection and receptor-proximal signaling complex regulation.

Molecular Function:

ubiquitin binding

Directly Involved In:

ubiquitin-dependent protein catabolic process interleukin-1-mediated signaling pathway innate immune response

Cellular Locations:

endosome cytosol

Supporting Evidence:

file:human/TOLLIP/TOLLIP-deep-research-falcon.md
**CUE domain (C-terminal; mapped as aa 231–274)**: 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
**TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB**: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NF‑κB signaling
file:human/TOLLIP/TOLLIP-deep-research-falcon.md
TOLLIP is a **non-enzymatic adaptor** whose primary biochemical capabilities are **specific binding interactions**:

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

PMID:1085432

Malignant lymphoma and rheumatic symptoms.

PMID:10854325

Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor.

PMID:11397809

IRAK1b, a novel alternative splice variant of interleukin-1 receptor-associated kinase (IRAK), mediates interleukin-1 signaling and has prolonged stability.

PMID:11441107

Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein A lipoprotein: role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor 2 signaling.

PMID:14563850

Tom1, a VHS domain-containing protein, interacts with tollip, ubiquitin, and clathrin.

PMID:15047686

Tollip and Tom1 form a complex and recruit ubiquitin-conjugated proteins onto early endosomes.

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network.

PMID:16412388

Recruitment of clathrin onto endosomes by the Tom1-Tollip complex.

PMID:16713569

A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

PMID:19060904

An empirical framework for binary interactome mapping.

PMID:19447967

Shifted Transversal Design smart-pooling for high coverage interactome mapping.

PMID:20936779

A human MAP kinase interactome.

PMID:21492153

Analysis of proteomic changes induced upon cellular differentiation of the human intestinal cell line Caco-2.

PMID:21903422

Mapping a dynamic innate immunity protein interaction network regulating type I interferon production.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:23533145

In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.

PMID:25042851

Autophagic clearance of polyQ proteins mediated by ubiquitin-Atg8 adaptors of the conserved CUET protein family.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:25910212

Widespread macromolecular interaction perturbations in human genetic disorders.

PMID:26320582

Tom1 Modulates Binding of Tollip to Phosphatidylinositol 3-Phosphate via a Coupled Folding and Binding Mechanism.

PMID:27107014

An inter-species protein-protein interaction network across vast evolutionary distance.

PMID:27368102

An ER-Associated Pathway Defines Endosomal Architecture for Controlled Cargo Transport.

PMID:31263572

Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease.

PMID:31515488

Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:34524948

Global Proximity Interactome of the Human Macroautophagy Pathway.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

Reactome:R-HSA-446634

IRAK4 is activated by autophosphorylation

Reactome:R-HSA-446684

IRAK2 is phosphorylated downstream of IRAK4 following IL1 receptor activation

Reactome:R-HSA-446692

IRAK1 binds to MYD88 within the IL1R complex

Reactome:R-HSA-446694

IRAK4 phosphorylates IRAK1

Reactome:R-HSA-446701

IRAK4-activated IRAK1 autophosphorylates

Reactome:R-HSA-446862

Hyperphosphorylated IRAK1 associates with TRAF6

Reactome:R-HSA-446868

The Interleukin 1 receptor complex binds Tollip

Reactome:R-HSA-446894

TRAF6 binding leads to IRAK1:TRAF6 release

Reactome:R-HSA-6798749

Exocytosis of specific granule lumen proteins

Reactome:R-HSA-6798751

Exocytosis of azurophil granule lumen proteins

file:human/TOLLIP/TOLLIP-deep-research-falcon.md

Falcon deep research synthesis for TOLLIP

Deep Research

Falcon

(TOLLIP-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 23 citations 2026-05-12T00:22:49.573276

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Human TOLLIP (UniProt Q9H0E2) functional annotation

0) Target verification (mandatory)

The literature synthesized here is restricted to human TOLLIP (Toll-interacting protein), consistent with UniProt accession Q9H0E2 and a ~274 aa adaptor protein organized around a phosphoinositide-binding C2 domain and a ubiquitin-binding CUE domain, with an N-terminal TOM1-binding domain and an experimentally mapped intrinsically disordered region (IDR) (hayashi2023tollipactsas pages 2-5, hayashi2023tollipactsas pages 5-6, baig2024adaptormoleculesmediate pages 8-9). Non-human “TOLLIP” studies exist (e.g., fish) and were not used to make claims about human molecular mechanisms beyond very general conservation context (tian2025fishtollipmanipulates pages 21-22).

1) Key concepts and definitions (current understanding)

1.1 What TOLLIP is

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/IL‑1R pathways) and (ii) sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation (baig2024adaptormoleculesmediate pages 8-9, hayashi2023tollipactsas pages 2-5, hayashi2023tollipactsas pages 1-2).

1.2 Domain architecture and domain-defined functions

Recent primary work provides a high-resolution functional decomposition of TOLLIP:
- TBD (TOM1-binding domain; ~aa 1–53): supports interaction with TOM1, with endosomal machinery including clathrin, and participates in recruitment of ubiquitinated cargo to early endosomes (baig2024adaptormoleculesmediate pages 8-9, hayashi2023tollipactsas pages 2-5).
- C2 domain (~central ~130 aa): binds phosphoinositides; in a 2023 mechanistic study, the C2 domain showed preferential interaction with PI3P and PI(4,5)P2, consistent with membrane/endosome targeting and PI3P-vesicle coupling (hayashi2023tollipactsas pages 5-6).
- IDR (intrinsically disordered region; mapped in 2023 study as aa 181–229): functions as a misfolding-sensing cargo-recognition module that can directly bind aberrant proteins (e.g., binding heat-denatured luciferase) and is required for certain lysosomal trafficking functions (hayashi2023tollipactsas pages 5-6, hayashi2023tollipactsas pages 17-18).
- CUE domain (C-terminal; mapped as aa 231–274): 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) (hayashi2023tollipactsas pages 5-6, baig2024adaptormoleculesmediate pages 8-9).

A figure-level schematic of this domain organization and a model of PI3P-dependent lysosomal trafficking are shown in Hayashi et al. 2023 (hayashi2023tollipactsas media 03df7429, hayashi2023tollipactsas media aced0de5).

Region (aa boundaries if available)	Domain/feature	Key binding partners/ligands	Main mechanistic role(s)	Evidence type	Key citations
1–53	TBD (TOM1-binding domain)	TOM1, clathrin, ubiquitin-conjugated cargo	Recruits TOM1/clathrin-linked endosomal sorting machinery; helps load ubiquitinated cargo onto early endosomes and supports endosome-to-lysosome trafficking	Domain annotation and interaction mapping from review; mutational/domain-mapping support in primary studies	(baig2024adaptormoleculesmediate pages 8-9, hayashi2023tollipactsas pages 2-5, hayashi2023tollipactsas media 03df7429)
~53–178 (central ~130 aa)	C2 domain	Phosphoinositides, especially PI3P and PI(4,5)P2; membranes/endosomes	Membrane targeting and anchoring of TOLLIP to PI3P-enriched vesicles/endosomes; required for PI3P-dependent lysosomal trafficking of aberrant membrane cargo; supports localization relevant to TLR/IL-1R trafficking control	Phospholipid-binding and mutagenesis data; localization assays; review synthesis	(forneris2025regulationofhost pages 15-19, baig2024adaptormoleculesmediate pages 8-9, hayashi2023tollipactsas pages 5-6, hayashi2023tollipactsas pages 2-5, hayashi2023tollipactsas media 03df7429)
181–229	IDR (intrinsically disordered region)	Misfolded/aberrant proteins (e.g., heat-denatured luciferase; aberrant ER membrane cargo such as A53T-HP)	Misfolding-sensing cargo-recognition module that directly binds aberrant proteins and enables selective lysosomal clearance without bulk ER turnover	Biochemical binding assays, mutagenesis, disorder prediction, lysosomal trafficking assays	(hayashi2023tollipactsas pages 5-6, hayashi2023tollipactsas pages 2-5, hayashi2023tollipactsas pages 1-2, hayashi2023tollipactsas pages 17-18, hayashi2023tollipactsas media 03df7429)
231–274	CUE domain	Ubiquitin chains/conjugates; IRAK1; TIR domains of IL-1R/TLR2/TLR4; BLK competes for the same interaction motif	Ubiquitin recognition; contributes to restraint of IRAK1 autophosphorylation in resting cells; links TOLLIP to IL-1R/TLR signaling complexes; supports cargo selection for lysosomal degradation	Mutagenesis and co-immunoprecipitation in primary studies; review synthesis	(forneris2025regulationofhost pages 15-19, baig2024adaptormoleculesmediate pages 8-9, hayashi2023tollipactsas pages 5-6, li2023blkpositivelyregulates pages 6-10, li2023blkpositivelyregulates pages 10-15)
Y76, Y86, Y152	Regulatory phosphotyrosine sites	BLK kinase; functionally affect IRAK1 association	BLK-mediated phosphorylation promotes dissociation of TOLLIP from IRAK1, exposing IRAK1 for hyperphosphorylation and enabling stronger IL-1R/TLR-driven NF-κB signaling and cytokine responses	Mass spectrometry-supported site identification, kinase assays, interaction assays, signaling assays, mouse genetics	(li2023blkpositivelyregulates pages 6-10, li2023blkpositivelyregulates pages 10-15, li2023blkpositivelyregulates pages 15-21, li2023blkpositivelyregulates pages 3-6)
Full-length protein / integrated domain action	Endosomal–lysosomal cargo adaptor	Ubiquitinated cargo, TOM1, clathrin, PI3P vesicles, lysosomal/endosomal compartments	Couples ubiquitinated and/or misfolded cargo to PI3P-dependent lysosomal trafficking; promotes degradation of aberrant ER membrane proteins and contributes to selective autophagy/protein quality control	Cell-based trafficking assays, KO/knockdown-rescue experiments, ultrastructural localization, review synthesis	(forneris2025regulationofhost pages 19-23, hayashi2023tollipactsas pages 2-5, hayashi2023tollipactsas pages 1-2, hayashi2023tollipactsas pages 17-18, baig2024adaptormoleculesmediate pages 18-19, hayashi2023tollipactsas media aced0de5)
Full-length protein / integrated domain action	Innate immune signaling adaptor-regulator	IRAK1, IL-1R, TLR2, TLR4, MyD88-pathway components, STING	Generally acts as a brake on IL-1R/TLR signaling in resting or homeostatic contexts by restraining IRAK1 and promoting receptor turnover; can also be switched to permit signaling after BLK-dependent phosphorylation; additionally implicated in STING homeostasis	Reviews plus mechanistic primary signaling study	(baig2024adaptormoleculesmediate pages 8-9, tian2025fishtollipmanipulates pages 21-22, li2023blkpositivelyregulates pages 6-10, baig2024adaptormoleculesmediate pages 9-11)

Table: This table summarizes the experimentally supported domain architecture of human TOLLIP and links each region to its major ligands, trafficking roles, and signaling functions. It is useful as a compact functional annotation anchored to recent mechanistic studies and authoritative reviews.

1.3 Cellular localization

TOLLIP’s 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 (hayashi2023tollipactsas pages 5-6, hayashi2023tollipactsas pages 2-5). In the context of aberrant ER membrane cargo, TOLLIP operates at the ER surface to capture client proteins and route them into RAB7/LAMP1-positive endolysosomal compartments (hayashi2023tollipactsas pages 2-5). A review additionally notes context-dependent translocation (e.g., low-dose LPS driving relocation from lysosomes to mitochondria with ROS consequences), emphasizing that localization can be dynamic under inflammatory conditions (baig2024adaptormoleculesmediate pages 8-9).

2) Recent developments and latest research (prioritizing 2023–2024)

2.1 (Dec 2023) A phosphorylation “switch” that converts TOLLIP from a brake to a permissive factor for TLR/IL‑1R signaling

Li et al. (Journal of Cell Biology; published Dec 2023; https://doi.org/10.1083/jcb.202302081) identified BLK as a kinase that phosphorylates TOLLIP on Y76, Y86, and Y152 (li2023blkpositivelyregulates pages 6-10). Mechanistically:
- In resting cells, TOLLIP forms a constitutive complex with IRAK1 and restrains IRAK1 phosphorylation (li2023blkpositivelyregulates pages 6-10).
- Upon IL‑1β stimulation, BLK is activated, binds the CUE domain of TOLLIP (with ~10-fold higher affinity than IRAK1), and phosphorylates TOLLIP at Y76/Y86/Y152 (li2023blkpositivelyregulates pages 6-10).
- BLK binding and phosphorylation promote dissociation of TOLLIP from IRAK1, exposing IRAK1 phosphorylation sites (ProST region) and enabling IRAK1 hyperphosphorylation, downstream NF‑κB activation, and inflammatory cytokine responses (li2023blkpositivelyregulates pages 6-10, li2023blkpositivelyregulates pages 10-15).
Physiological relevance was supported by in vivo phenotypes where Blk−/− mice produced fewer inflammatory cytokines and showed increased resistance to IL‑1β-induced death (li2023blkpositivelyregulates pages 6-10).

This study reframes TOLLIP not only as a negative regulator but as a regulated checkpoint node whose inhibitory complex can be actively dismantled by a receptor-proximal kinase to permit robust signaling.

2.2 (Nov 2023) TOLLIP as a cargo adaptor for selective lysosomal degradation of aberrant ER membrane proteins

Hayashi et al. (The EMBO Journal; published Nov 2023; https://doi.org/10.15252/embj.2023114272) provided a mechanistic model in which TOLLIP is a cargo-specific adaptor for the lysosomal removal of aberrant ER membrane proteins (hayashi2023tollipactsas pages 1-2).

Key findings:
- TOLLIP promotes selective lysosomal degradation of aberrant membrane proteins (including a model A53T-HP substrate and disease mutants of VAPB and Seipin) (hayashi2023tollipactsas pages 1-2).
- Cargo recognition requires a misfolding-sensing IDR and a ubiquitin-binding CUE domain; deletion/mutation of these regions disrupts binding to ubiquitin conjugates and interaction with aberrant cargo (hayashi2023tollipactsas pages 5-6, hayashi2023tollipactsas pages 1-2).
- The C2 domain links TOLLIP to PI3P-dependent trafficking, enabling delivery to endolysosomal compartments; this pathway is selective for aberrant cargos and does not drive bulk ER turnover (hayashi2023tollipactsas pages 2-5, hayashi2023tollipactsas pages 1-2).
- Functionally, TOLLIP depletion exacerbated ER stress when ERAD was inhibited, suggesting TOLLIP-mediated lysosomal quality control operates in parallel with ERAD to safeguard ER proteostasis (hayashi2023tollipactsas pages 1-2).

This 2023 study expanded TOLLIP’s functional annotation beyond innate immunity into a direct mechanistic role in ER membrane protein quality control.

2.3 (Feb 2024) Expert synthesis: TOLLIP as a “multitasking” adaptor coordinating negative regulation and trafficking

Baig et al. (Frontiers in Immunology; published Feb 2024; https://doi.org/10.3389/fimmu.2024.1355012) review adaptor molecules that negatively regulate macrophage inflammatory pathways and describe TOLLIP as a ubiquitously expressed adaptor that modulates IL‑1R and TLR2/4 signaling and interacts directly with TLR2/TLR4 (baig2024adaptormoleculesmediate pages 8-9). The review emphasizes a canonical negative-regulatory role in acute inflammatory signaling—via interactions with IRAKs and receptor TIR domains and via promoting receptor degradation—while noting context-dependence and additional roles in trafficking/autophagy-related processes (baig2024adaptormoleculesmediate pages 8-9, baig2024adaptormoleculesmediate pages 9-11).

3) Current applications and real-world implementations

3.1 Clinical trial implementation: genotyping TOLLIP SNPs as a candidate modifier of N-acetylcysteine (NAC) response

A completed Phase 1 clinical trial in retinitis pigmentosa, FIGHT‑RP1 (ClinicalTrials.gov NCT03063021; start date 2017-02-15, completion date 2019-02-11) tested oral N‑acetylcysteine (NAC) and explicitly planned DNA collection to genotype the same TOLLIP SNPs previously reported as influencing NAC response in idiopathic pulmonary fibrosis (IPF), as a candidate-gene analysis (NCT03063021 chunk 1). The trial also banks RNA for future transcriptomic studies (NCT03063021 chunk 1). Trial URL: https://clinicaltrials.gov/study/NCT03063021.

Importantly, this trial does not target TOLLIP directly, but illustrates how TOLLIP human genetics can be operationalized as a therapeutic-response modifier in an interventional study design (NCT03063021 chunk 1).

3.2 Translational disease associations (target–disease knowledgebases)

Open Targets lists TOLLIP (ENSG00000078902) association evidence across respiratory and other diseases, including idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, with disease-association scores (e.g., COPD score ~0.142; IPF score ~0.374 in the returned Open Targets snapshot) (OpenTargets Search: -TOLLIP). While such associations are not mechanistic proof, they highlight settings where TOLLIP biology and/or genetics are considered relevant for human disease prioritization.

4) Expert opinions and analysis (authoritative sources)

4.1 Consensus view: adaptor integrating ubiquitin, membranes, and receptor signaling

The 2024 review frames TOLLIP as a “multitasking” adaptor that links ubiquitin, endosomal trafficking machinery (TOM1/clathrin), and innate immune receptor signaling to restrain inflammatory outputs, including by limiting IRAK activation and promoting receptor turnover (baig2024adaptormoleculesmediate pages 8-9, baig2024adaptormoleculesmediate pages 9-11). This aligns with the mechanistic picture from 2023 primary studies in which specific TOLLIP domains encode: phosphoinositide-directed localization (C2), ubiquitin recognition (CUE), and client recognition (IDR) (hayashi2023tollipactsas pages 5-6, hayashi2023tollipactsas pages 1-2).

4.2 Updated 2023–2024 perspective: “negative regulator” is accurate but incomplete

Two 2023 studies sharpen (and partially complicate) the traditional “TOLLIP is a negative regulator” label:
- In TLR/IL‑1R pathways, TOLLIP can function as an inhibitory clamp on IRAK1 in resting cells but is actively displaced by BLK after receptor engagement to permit efficient signal propagation—an explicit regulatory switch rather than a static inhibitor (li2023blkpositivelyregulates pages 6-10).
- In proteostasis, TOLLIP is not simply an autophagy receptor; it can act as a cargo-specific adaptor for PI3P-dependent lysosomal trafficking of aberrant ER membrane proteins, with domain-level specificity and separability from bulk ER-phagy (hayashi2023tollipactsas pages 1-2, hayashi2023tollipactsas media aced0de5).

5) Relevant statistics and data points from recent studies

5.1 Quantitative trafficking readouts (Hayashi et al., EMBO J 2023)

Hayashi et al. quantified endosomal/lysosomal features and lysosomal delivery using operational metrics, including:
- Definition of “acidic puncta” as mCherry:EGFP intensity ratio > 1.25 in mCherry‑EGFP cargo assays (hayashi2023tollipactsas pages 17-18).
- Example reported puncta counts: average PI3P puncta per cell changed from 38 (siCtrl) to 33 (siTOLLIP) in one condition set; additional construct-dependent values were reported (e.g., 39 CFP; 36 WT; 37 C2mut; 48 IDRmut; 37 ΔCUE) (hayashi2023tollipactsas pages 17-18).
- Example LAMP1 puncta averages reported across conditions included 50 (siCtrl) vs 33 (siTOLLIP), with partial rescue by WT and differing impacts of mutants (e.g., 32 siTOLLIP+WT; 28 siTOLLIP+C2mut #1; 38 siTOLLIP+IDRmut) (hayashi2023tollipactsas pages 17-18).
These data support that TOLLIP perturbation measurably affects PI3P/LAMP1-associated trafficking features in cells, consistent with its PI3P-dependent lysosomal routing role (hayashi2023tollipactsas pages 2-5, hayashi2023tollipactsas pages 17-18).

5.2 Sample sizes and quantitative design features (Li et al., JCB 2023)

Li et al. report typical experimental replication for signaling outputs, including qPCR with n=3 technical replicates, luciferase assays with n=3 biological replicates, and ELISA with n=6 biological replicates, and they use Kaplan–Meier/log-rank tests for survival analyses in mouse studies (li2023blkpositivelyregulates pages 6-10). While many fold-changes are figure-embedded (not present in the excerpt), key quantitative mechanistic claims include BLK’s ~10-fold higher affinity for TOLLIP than IRAK1 in their binding analyses (li2023blkpositivelyregulates pages 6-10).

5.3 Quantitative association signals (Open Targets snapshot)

Open Targets returned disease-association scores for TOLLIP such as ~0.374 (idiopathic pulmonary fibrosis) and ~0.142 (COPD) in the snapshot retrieved here (OpenTargets Search: -TOLLIP). These scores are integrative/knowledgebase-derived rather than a single study statistic, and should be interpreted accordingly.

Mechanistic functional annotation summary (human TOLLIP/Q9H0E2)

Primary molecular function

TOLLIP is a non-enzymatic adaptor whose primary biochemical capabilities are specific binding interactions:
1) Phosphoinositide binding (C2 domain; PI3P/PI(4,5)P2) that localizes TOLLIP to appropriate membranes/vesicles and enables PI3P-dependent trafficking (hayashi2023tollipactsas pages 5-6).
2) Ubiquitin binding (CUE domain), enabling recognition of ubiquitinated cargo and coupling to degradation pathways; in immune signaling contexts the CUE domain is also implicated in interactions with IRAKs and receptor TIR domains (hayashi2023tollipactsas pages 5-6, baig2024adaptormoleculesmediate pages 8-9).
3) Misfolded client recognition (IDR), supporting selective capture of aberrant proteins for lysosomal trafficking (hayashi2023tollipactsas pages 5-6).

Cellular sites of action

Endosomes / PI3P-enriched vesicles and endolysosomes, supporting receptor/cargo sorting and degradation (hayashi2023tollipactsas pages 5-6, hayashi2023tollipactsas pages 2-5).
ER surface, where TOLLIP can recognize aberrant membrane proteins and route them to lysosomes (hayashi2023tollipactsas pages 2-5).
Potentially dynamic relocalization under inflammatory contexts (e.g., mitochondria translocation described in review synthesis) (baig2024adaptormoleculesmediate pages 8-9).

Major pathways

TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB: TOLLIP restrains IRAK1 in resting cells; BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger NF‑κB signaling (li2023blkpositivelyregulates pages 6-10, li2023blkpositivelyregulates pages 10-15).
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 (hayashi2023tollipactsas pages 1-2).

Key 2023–2024 references (URLs and dates)

Hayashi Y. et al. “TOLLIP acts as a cargo adaptor to promote lysosomal degradation of aberrant ER membrane proteins.” The EMBO Journal (Nov 2023). https://doi.org/10.15252/embj.2023114272 (hayashi2023tollipactsas pages 1-2)
Li W‑W. et al. “BLK positively regulates TLR/IL‑1R signaling by catalyzing TOLLIP phosphorylation.” The Journal of Cell Biology (Dec 2023). https://doi.org/10.1083/jcb.202302081 (li2023blkpositivelyregulates pages 6-10)
Baig M.S. et al. “Adaptor molecules mediate negative regulation of macrophage inflammatory pathways: a closer look.” Frontiers in Immunology (Feb 2024). https://doi.org/10.3389/fimmu.2024.1355012 (baig2024adaptormoleculesmediate pages 8-9)
ClinicalTrials.gov: NCT03063021 (FIGHT‑RP1; NAC in retinitis pigmentosa; includes TOLLIP SNP genotyping plan). First posted 2017; completed 2019. https://clinicaltrials.gov/study/NCT03063021 (NCT03063021 chunk 1)
Open Targets Platform (accessed via tool snapshot): disease–target associations for TOLLIP including IPF/COPD (OpenTargets Search: -TOLLIP)

Notable evidence gaps (based on retrieved sources)

Within the retrieved 2023–2024 corpus, explicit human-variant (SNP-level) effect sizes for specific TOLLIP polymorphisms and their mechanistic consequences were not available as full-text evidence; the clinical trial record confirms such polymorphisms are considered actionable for NAC response in IPF, but the underlying genetic association details would require direct access to the cited IPF pharmacogenetic studies (NCT03063021 chunk 1).

References

(hayashi2023tollipactsas pages 2-5): Yuki Hayashi, Sho Takatori, Waleed Y Warsame, Taisuke Tomita, Takao Fujisawa, and Hidenori Ichijo. Tollip acts as a cargo adaptor to promote lysosomal degradation of aberrant er membrane proteins. The EMBO Journal, Nov 2023. URL: https://doi.org/10.15252/embj.2023114272, doi:10.15252/embj.2023114272. This article has 25 citations.
(hayashi2023tollipactsas pages 5-6): Yuki Hayashi, Sho Takatori, Waleed Y Warsame, Taisuke Tomita, Takao Fujisawa, and Hidenori Ichijo. Tollip acts as a cargo adaptor to promote lysosomal degradation of aberrant er membrane proteins. The EMBO Journal, Nov 2023. URL: https://doi.org/10.15252/embj.2023114272, doi:10.15252/embj.2023114272. This article has 25 citations.
(baig2024adaptormoleculesmediate pages 8-9): Mirza S. Baig, Spyridoula Barmpoutsi, Shreya Bharti, Andreas Weigert, Nik Hirani, Rajat Atre, Rakhi Khabiya, Rahul Sharma, Shivmuni Sarup, and Rajkumar Savai. Adaptor molecules mediate negative regulation of macrophage inflammatory pathways: a closer look. Frontiers in Immunology, Feb 2024. URL: https://doi.org/10.3389/fimmu.2024.1355012, doi:10.3389/fimmu.2024.1355012. This article has 7 citations and is from a peer-reviewed journal.
(tian2025fishtollipmanipulates pages 21-22): Meng-Ze Tian, Yang-Yang Wang, Bao-jie Cui, Xiao Xu, Chu-Jing Zhou, Can Zhang, Zhuo-Cong Li, Meng-Qian Hong, Na Xu, Dan-Dan Chen, Long-Feng Lu, and Shun Li. Fish tollip manipulates atg5 for autophagic degradation of sting to attenuate antiviral interferon responses. PLOS Pathogens, 21:e1013512, Sep 2025. URL: https://doi.org/10.1371/journal.ppat.1013512, doi:10.1371/journal.ppat.1013512. This article has 1 citations and is from a highest quality peer-reviewed journal.
(hayashi2023tollipactsas pages 1-2): Yuki Hayashi, Sho Takatori, Waleed Y Warsame, Taisuke Tomita, Takao Fujisawa, and Hidenori Ichijo. Tollip acts as a cargo adaptor to promote lysosomal degradation of aberrant er membrane proteins. The EMBO Journal, Nov 2023. URL: https://doi.org/10.15252/embj.2023114272, doi:10.15252/embj.2023114272. This article has 25 citations.
(hayashi2023tollipactsas pages 17-18): Yuki Hayashi, Sho Takatori, Waleed Y Warsame, Taisuke Tomita, Takao Fujisawa, and Hidenori Ichijo. Tollip acts as a cargo adaptor to promote lysosomal degradation of aberrant er membrane proteins. The EMBO Journal, Nov 2023. URL: https://doi.org/10.15252/embj.2023114272, doi:10.15252/embj.2023114272. This article has 25 citations.
(hayashi2023tollipactsas media 03df7429): Yuki Hayashi, Sho Takatori, Waleed Y Warsame, Taisuke Tomita, Takao Fujisawa, and Hidenori Ichijo. Tollip acts as a cargo adaptor to promote lysosomal degradation of aberrant er membrane proteins. The EMBO Journal, Nov 2023. URL: https://doi.org/10.15252/embj.2023114272, doi:10.15252/embj.2023114272. This article has 25 citations.
(hayashi2023tollipactsas media aced0de5): Yuki Hayashi, Sho Takatori, Waleed Y Warsame, Taisuke Tomita, Takao Fujisawa, and Hidenori Ichijo. Tollip acts as a cargo adaptor to promote lysosomal degradation of aberrant er membrane proteins. The EMBO Journal, Nov 2023. URL: https://doi.org/10.15252/embj.2023114272, doi:10.15252/embj.2023114272. This article has 25 citations.
(forneris2025regulationofhost pages 15-19): P Forneris. Regulation of host immune responses by toll-interacting protein during citrobacter rodentium infection. Unknown journal, 2025.
(li2023blkpositivelyregulates pages 6-10): Wei-Wei Li, Xu-Xu Fan, Zhi-Sheng Xu, Zi-Xiang Zhu, Zhao-Yu Zhu, Xue-Jing Cao, Dan-Shi Pei, Yi-Zhuo Wang, Ji-Yan Zhang, Yan-Yi Wang, and Hai-Xue Zheng. Blk positively regulates tlr/il-1r signaling by catalyzing tollip phosphorylation. The Journal of Cell Biology, Dec 2023. URL: https://doi.org/10.1083/jcb.202302081, doi:10.1083/jcb.202302081. This article has 4 citations.
(li2023blkpositivelyregulates pages 10-15): Wei-Wei Li, Xu-Xu Fan, Zhi-Sheng Xu, Zi-Xiang Zhu, Zhao-Yu Zhu, Xue-Jing Cao, Dan-Shi Pei, Yi-Zhuo Wang, Ji-Yan Zhang, Yan-Yi Wang, and Hai-Xue Zheng. Blk positively regulates tlr/il-1r signaling by catalyzing tollip phosphorylation. The Journal of Cell Biology, Dec 2023. URL: https://doi.org/10.1083/jcb.202302081, doi:10.1083/jcb.202302081. This article has 4 citations.
(li2023blkpositivelyregulates pages 15-21): Wei-Wei Li, Xu-Xu Fan, Zhi-Sheng Xu, Zi-Xiang Zhu, Zhao-Yu Zhu, Xue-Jing Cao, Dan-Shi Pei, Yi-Zhuo Wang, Ji-Yan Zhang, Yan-Yi Wang, and Hai-Xue Zheng. Blk positively regulates tlr/il-1r signaling by catalyzing tollip phosphorylation. The Journal of Cell Biology, Dec 2023. URL: https://doi.org/10.1083/jcb.202302081, doi:10.1083/jcb.202302081. This article has 4 citations.
(li2023blkpositivelyregulates pages 3-6): Wei-Wei Li, Xu-Xu Fan, Zhi-Sheng Xu, Zi-Xiang Zhu, Zhao-Yu Zhu, Xue-Jing Cao, Dan-Shi Pei, Yi-Zhuo Wang, Ji-Yan Zhang, Yan-Yi Wang, and Hai-Xue Zheng. Blk positively regulates tlr/il-1r signaling by catalyzing tollip phosphorylation. The Journal of Cell Biology, Dec 2023. URL: https://doi.org/10.1083/jcb.202302081, doi:10.1083/jcb.202302081. This article has 4 citations.
(forneris2025regulationofhost pages 19-23): P Forneris. Regulation of host immune responses by toll-interacting protein during citrobacter rodentium infection. Unknown journal, 2025.
(baig2024adaptormoleculesmediate pages 18-19): Mirza S. Baig, Spyridoula Barmpoutsi, Shreya Bharti, Andreas Weigert, Nik Hirani, Rajat Atre, Rakhi Khabiya, Rahul Sharma, Shivmuni Sarup, and Rajkumar Savai. Adaptor molecules mediate negative regulation of macrophage inflammatory pathways: a closer look. Frontiers in Immunology, Feb 2024. URL: https://doi.org/10.3389/fimmu.2024.1355012, doi:10.3389/fimmu.2024.1355012. This article has 7 citations and is from a peer-reviewed journal.
(baig2024adaptormoleculesmediate pages 9-11): Mirza S. Baig, Spyridoula Barmpoutsi, Shreya Bharti, Andreas Weigert, Nik Hirani, Rajat Atre, Rakhi Khabiya, Rahul Sharma, Shivmuni Sarup, and Rajkumar Savai. Adaptor molecules mediate negative regulation of macrophage inflammatory pathways: a closer look. Frontiers in Immunology, Feb 2024. URL: https://doi.org/10.3389/fimmu.2024.1355012, doi:10.3389/fimmu.2024.1355012. This article has 7 citations and is from a peer-reviewed journal.
(NCT03063021 chunk 1): The FIGHT-RP1 Study. Johns Hopkins University. 2017. ClinicalTrials.gov Identifier: NCT03063021
(OpenTargets Search: -TOLLIP): Open Targets Query (-TOLLIP, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

Citations

tian2025fishtollipmanipulates pages 21-22
hayashi2023tollipactsas pages 5-6
hayashi2023tollipactsas pages 2-5
baig2024adaptormoleculesmediate pages 8-9
li2023blkpositivelyregulates pages 6-10
hayashi2023tollipactsas pages 1-2
hayashi2023tollipactsas pages 17-18
forneris2025regulationofhost pages 15-19
li2023blkpositivelyregulates pages 10-15
li2023blkpositivelyregulates pages 15-21
li2023blkpositivelyregulates pages 3-6
forneris2025regulationofhost pages 19-23
baig2024adaptormoleculesmediate pages 18-19
baig2024adaptormoleculesmediate pages 9-11
https://doi.org/10.1083/jcb.202302081
https://doi.org/10.15252/embj.2023114272
https://doi.org/10.3389/fimmu.2024.1355012
https://clinicaltrials.gov/study/NCT03063021.
https://clinicaltrials.gov/study/NCT03063021
https://doi.org/10.15252/embj.2023114272,
https://doi.org/10.3389/fimmu.2024.1355012,
https://doi.org/10.1371/journal.ppat.1013512,
https://doi.org/10.1083/jcb.202302081,

📄 View Raw YAML

id: Q9H0E2
gene_symbol: TOLLIP
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: '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.'
alternative_products:
- id: Q9H0E2-1
  name: '1'
- id: Q9H0E2-2
  name: '2'
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Cytoplasm is the broad cellular compartment for TOLLIP adaptor activity and endosomal
      trafficking.
    action: ACCEPT
    reason: cytoplasm is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate
      immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Ubiquitin-dependent protein catabolic process is supported by TOLLIP-mediated routing
      of ubiquitinated or aberrant cargo to endolysosomal degradation.
    action: ACCEPT
    reason: ubiquitin-dependent protein catabolic process is supported as part of TOLLIP adaptor,
      endosomal cargo-routing, or innate immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**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'
- term:
    id: GO:0031624
    label: ubiquitin conjugating enzyme binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: The evidence supports CUE-domain recognition of ubiquitin conjugates rather than a
      specific ubiquitin-conjugating enzyme binding function.
    action: MODIFY
    reason: ubiquitin conjugating enzyme binding is less precise than the supported TOLLIP
      mechanism.
    proposed_replacement_terms:
    - id: GO:0043130
      label: ubiquitin binding
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0043130
    label: ubiquitin binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Ubiquitin binding is a core CUE-domain molecular function of TOLLIP.
    action: ACCEPT
    reason: ubiquitin binding is supported as part of TOLLIP adaptor, endosomal cargo-routing, or
      innate immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
- term:
    id: GO:0002376
    label: immune system process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: immune system process is plausible as a context-specific or secondary TOLLIP-associated
      annotation, but it is not the most precise core function.
    action: KEEP_AS_NON_CORE
    reason: immune system process is secondary to TOLLIP ubiquitin/membrane adaptor and TLR/IL-1R
      signaling roles.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB**: TOLLIP restrains IRAK1 in resting cells;
        BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger
        NF‑κB signaling'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Cytoplasm is the broad cellular compartment for TOLLIP adaptor activity and endosomal
      trafficking.
    action: ACCEPT
    reason: cytoplasm is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate
      immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0005768
    label: endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Endosome localization is central to TOLLIP PI3P-dependent cargo routing.
    action: ACCEPT
    reason: endosome is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate
      immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**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'
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Early endosome localization is supported by TOLLIP coupling of PI3P vesicles to cargo
      trafficking.
    action: ACCEPT
    reason: early endosome is supported as part of TOLLIP adaptor, endosomal cargo-routing, or
      innate immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**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'
- term:
    id: GO:0006914
    label: autophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: autophagy is plausible as a context-specific or secondary TOLLIP-associated annotation,
      but it is not the most precise core function.
    action: KEEP_AS_NON_CORE
    reason: autophagy is secondary to TOLLIP ubiquitin/membrane adaptor and TLR/IL-1R signaling
      roles.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**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'
- term:
    id: GO:0006954
    label: inflammatory response
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: inflammatory response is plausible as a context-specific or secondary TOLLIP-associated
      annotation, but it is not the most precise core function.
    action: KEEP_AS_NON_CORE
    reason: inflammatory response is secondary to TOLLIP ubiquitin/membrane adaptor and TLR/IL-1R
      signaling roles.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB**: TOLLIP restrains IRAK1 in resting cells;
        BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger
        NF‑κB signaling'
- term:
    id: GO:0043130
    label: ubiquitin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Ubiquitin binding is a core CUE-domain molecular function of TOLLIP.
    action: ACCEPT
    reason: ubiquitin binding is supported as part of TOLLIP adaptor, endosomal cargo-routing, or
      innate immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
- term:
    id: GO:0045087
    label: innate immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Innate immune response is supported through TOLLIP regulation of TLR/IL-1R signaling
      outputs.
    action: ACCEPT
    reason: innate immune response is supported as part of TOLLIP adaptor, endosomal cargo-routing,
      or innate immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB**: TOLLIP restrains IRAK1 in resting cells;
        BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger
        NF‑κB signaling'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14563850
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16713569
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19060904
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19447967
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20936779
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21903422
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25042851
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27107014
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34524948
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005150
    label: interleukin-1, type I receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Interleukin-1 type I receptor binding is supported as part of the IL-1R/TLR signaling
      adaptor-regulator role.
    action: ACCEPT
    reason: interleukin-1, type I receptor binding is supported as part of TOLLIP adaptor, endosomal
      cargo-routing, or innate immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB**: TOLLIP restrains IRAK1 in resting cells;
        BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger
        NF‑κB signaling'
- term:
    id: GO:0016604
    label: nuclear body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: nuclear body is plausible as a context-specific or secondary TOLLIP-associated
      annotation, but it is not the most precise core function.
    action: KEEP_AS_NON_CORE
    reason: nuclear body is secondary to TOLLIP ubiquitin/membrane adaptor and TLR/IL-1R signaling
      roles.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**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'
- term:
    id: GO:0031624
    label: ubiquitin conjugating enzyme binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: The evidence supports CUE-domain recognition of ubiquitin conjugates rather than a
      specific ubiquitin-conjugating enzyme binding function.
    action: MODIFY
    reason: ubiquitin conjugating enzyme binding is less precise than the supported TOLLIP
      mechanism.
    proposed_replacement_terms:
    - id: GO:0043130
      label: ubiquitin binding
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ubiquitin protein ligase binding is not the main supported activity; the reviewed
      evidence emphasizes ubiquitin conjugate binding and adaptor function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ubiquitin protein ligase binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0032183
    label: SUMO binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: SUMO binding is not supported by the Falcon synthesis as a core or well-grounded TOLLIP
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: SUMO binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Protein-containing complex is supported because TOLLIP acts in TOM1/clathrin, cargo,
      IRAK, and receptor-proximal complexes.
    action: ACCEPT
    reason: protein-containing complex is supported as part of TOLLIP adaptor, endosomal
      cargo-routing, or innate immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB**: TOLLIP restrains IRAK1 in resting cells;
        BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger
        NF‑κB signaling'
- term:
    id: GO:0033235
    label: positive regulation of protein sumoylation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Positive regulation of protein sumoylation is not supported as a TOLLIP core function
      in the reviewed evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: positive regulation of protein sumoylation overstates or obscures the supported TOLLIP
      function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: perinuclear region of cytoplasm is secondary to TOLLIP ubiquitin/membrane adaptor and
      TLR/IL-1R signaling roles.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**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'
- term:
    id: GO:0070498
    label: interleukin-1-mediated signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Interleukin-1-mediated signaling pathway is a supported core immune-signaling context
      for TOLLIP.
    action: ACCEPT
    reason: interleukin-1-mediated signaling pathway is supported as part of TOLLIP adaptor,
      endosomal cargo-routing, or innate immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB**: TOLLIP restrains IRAK1 in resting cells;
        BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger
        NF‑κB signaling'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal
      and receptor-signaling compartments.
    action: ACCEPT
    reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate
      immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26320582
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31263572
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15047686
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0019897
    label: extrinsic component of plasma membrane
  evidence_type: IC
  original_reference_id: PMID:10854325
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: extrinsic component of plasma membrane is secondary to TOLLIP ubiquitin/membrane adaptor
      and TLR/IL-1R signaling roles.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**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'
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:10854325
  review:
    summary: Molecular adaptor activity captures the core TOLLIP role in linking cargo, endosomal
      membranes, and receptor-signaling proteins.
    action: ACCEPT
    reason: molecular adaptor activity is supported as part of TOLLIP adaptor, endosomal
      cargo-routing, or innate immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**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'
- term:
    id: GO:0070498
    label: interleukin-1-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:10854325
  review:
    summary: Interleukin-1-mediated signaling pathway is a supported core immune-signaling context
      for TOLLIP.
    action: ACCEPT
    reason: interleukin-1-mediated signaling pathway is supported as part of TOLLIP adaptor,
      endosomal cargo-routing, or innate immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB**: TOLLIP restrains IRAK1 in resting cells;
        BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger
        NF‑κB signaling'
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:27368102
  review:
    summary: Molecular adaptor activity captures the core TOLLIP role in linking cargo, endosomal
      membranes, and receptor-signaling proteins.
    action: ACCEPT
    reason: molecular adaptor activity is supported as part of TOLLIP adaptor, endosomal
      cargo-routing, or innate immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**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'
- term:
    id: GO:0019900
    label: kinase binding
  evidence_type: IPI
  original_reference_id: PMID:10854325
  review:
    summary: Kinase binding is supported by TOLLIP interactions with IRAK1 and BLK in
      receptor-proximal signaling control.
    action: ACCEPT
    reason: kinase binding is supported as part of TOLLIP adaptor, endosomal cargo-routing, or
      innate immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB**: TOLLIP restrains IRAK1 in resting cells;
        BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger
        NF‑κB signaling'
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: BLK binding and phosphorylation promote **dissociation of TOLLIP from
        IRAK1**, exposing IRAK1 phosphorylation sites (ProST region) and enabling **IRAK1
        hyperphosphorylation**, downstream **NF‑κB activation**, and inflammatory cytokine responses
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:10854325
  review:
    summary: Protein-containing complex is supported because TOLLIP acts in TOM1/clathrin, cargo,
      IRAK, and receptor-proximal complexes.
    action: ACCEPT
    reason: protein-containing complex is supported as part of TOLLIP adaptor, endosomal
      cargo-routing, or innate immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB**: TOLLIP restrains IRAK1 in resting cells;
        BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger
        NF‑κB signaling'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11397809
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798749
  review:
    summary: Extracellular region is inconsistent with the reviewed intracellular adaptor/endosomal
      functions of TOLLIP.
    action: MARK_AS_OVER_ANNOTATED
    reason: extracellular region overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  review:
    summary: Extracellular region is inconsistent with the reviewed intracellular adaptor/endosomal
      functions of TOLLIP.
    action: MARK_AS_OVER_ANNOTATED
    reason: extracellular region overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0035578
    label: azurophil granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  review:
    summary: Azurophil granule lumen is a context-specific secretory-granule annotation and is not
      supported as a functional TOLLIP location.
    action: MARK_AS_OVER_ANNOTATED
    reason: azurophil granule lumen overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0035580
    label: specific granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798749
  review:
    summary: Specific granule lumen is a context-specific secretory-granule annotation and is not
      supported as a functional TOLLIP location.
    action: MARK_AS_OVER_ANNOTATED
    reason: specific granule lumen overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  review:
    summary: Extracellular exosome detection does not represent the core intracellular adaptor
      function of TOLLIP.
    action: MARK_AS_OVER_ANNOTATED
    reason: extracellular exosome overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0030855
    label: epithelial cell differentiation
  evidence_type: IEP
  original_reference_id: PMID:21492153
  review:
    summary: epithelial cell differentiation is plausible as a context-specific or secondary
      TOLLIP-associated annotation, but it is not the most precise core function.
    action: KEEP_AS_NON_CORE
    reason: epithelial cell differentiation is secondary to TOLLIP ubiquitin/membrane adaptor and
      TLR/IL-1R signaling roles.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**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'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16412388
  review:
    summary: Protein binding is too generic for TOLLIP; specific adaptor, ubiquitin-binding,
      receptor-binding, and kinase-binding terms better capture the mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
- term:
    id: GO:0036010
    label: protein localization to endosome
  evidence_type: IDA
  original_reference_id: PMID:16412388
  review:
    summary: Protein localization to endosome is supported by the TOLLIP cargo-routing mechanism.
    action: ACCEPT
    reason: protein localization to endosome is supported as part of TOLLIP adaptor, endosomal
      cargo-routing, or innate immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**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'
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  review:
    summary: Extracellular exosome detection does not represent the core intracellular adaptor
      function of TOLLIP.
    action: MARK_AS_OVER_ANNOTATED
    reason: extracellular exosome overstates or obscures the supported TOLLIP function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446634
  review:
    summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal
      and receptor-signaling compartments.
    action: ACCEPT
    reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate
      immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446684
  review:
    summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal
      and receptor-signaling compartments.
    action: ACCEPT
    reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate
      immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446692
  review:
    summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal
      and receptor-signaling compartments.
    action: ACCEPT
    reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate
      immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446694
  review:
    summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal
      and receptor-signaling compartments.
    action: ACCEPT
    reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate
      immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446701
  review:
    summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal
      and receptor-signaling compartments.
    action: ACCEPT
    reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate
      immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446862
  review:
    summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal
      and receptor-signaling compartments.
    action: ACCEPT
    reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate
      immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446868
  review:
    summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal
      and receptor-signaling compartments.
    action: ACCEPT
    reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate
      immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446894
  review:
    summary: Cytosol is consistent with TOLLIP acting as a soluble adaptor recruited to endosomal
      and receptor-signaling compartments.
    action: ACCEPT
    reason: cytosol is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate
      immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IC
  original_reference_id: PMID:11441107
  review:
    summary: Cytoplasm is the broad cellular compartment for TOLLIP adaptor activity and endosomal
      trafficking.
    action: ACCEPT
    reason: cytoplasm is supported as part of TOLLIP adaptor, endosomal cargo-routing, or innate
      immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: TOLLIP’s 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
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IPI
  original_reference_id: PMID:11441107
  review:
    summary: Generic signal transduction should be refined to the IL-1R/TLR receptor signaling
      context supported for TOLLIP.
    action: MODIFY
    reason: signal transduction is less precise than the supported TOLLIP mechanism.
    proposed_replacement_terms:
    - id: GO:0070498
      label: interleukin-1-mediated signaling pathway
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB**: TOLLIP restrains IRAK1 in resting cells;
        BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger
        NF‑κB signaling'
- term:
    id: GO:0035325
    label: Toll-like receptor binding
  evidence_type: IPI
  original_reference_id: PMID:11441107
  review:
    summary: Toll-like receptor binding is supported as part of TOLLIP receptor-proximal innate
      immune signaling regulation.
    action: ACCEPT
    reason: Toll-like receptor binding is supported as part of TOLLIP adaptor, endosomal
      cargo-routing, or innate immune signaling function.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB**: TOLLIP restrains IRAK1 in resting cells;
        BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger
        NF‑κB signaling'
- term:
    id: GO:0016310
    label: phosphorylation
  evidence_type: IDA
  original_reference_id: PMID:1085432
  review:
    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.
    action: REMOVE
    reason: TOLLIP is a phosphorylation-regulated adaptor, not an enzyme that catalyzes
      phosphorylation.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: BLK binding and phosphorylation promote **dissociation of TOLLIP from
        IRAK1**, exposing IRAK1 phosphorylation sites (ProST region) and enabling **IRAK1
        hyperphosphorylation**, downstream **NF‑κB activation**, and inflammatory cytokine responses
- term:
    id: GO:0045321
    label: leukocyte activation
  evidence_type: NAS
  original_reference_id: PMID:11441107
  review:
    summary: leukocyte activation is plausible as a context-specific or secondary TOLLIP-associated
      annotation, but it is not the most precise core function.
    action: KEEP_AS_NON_CORE
    reason: leukocyte activation is secondary to TOLLIP ubiquitin/membrane adaptor and TLR/IL-1R
      signaling roles.
    supported_by:
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: 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/IL‑1R pathways) and (ii)
        **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal
        degradation**
    - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
      supporting_text: '**TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB**: TOLLIP restrains IRAK1 in resting cells;
        BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger
        NF‑κB signaling'
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary
    mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using
    Ensembl Compara
  findings: []
- id: PMID:1085432
  title: Malignant lymphoma and rheumatic symptoms.
  findings: []
- id: PMID:10854325
  title: Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor.
  findings: []
- id: PMID:11397809
  title: IRAK1b, a novel alternative splice variant of interleukin-1 receptor-associated kinase
    (IRAK), mediates interleukin-1 signaling and has prolonged stability.
  findings: []
- id: PMID:11441107
  title: 'Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor
    and Borrelia burgdorferi outer surface protein A lipoprotein: role of Toll-interacting protein and
    IL-1 receptor signaling molecules in Toll-like receptor 2 signaling.'
  findings: []
- id: PMID:14563850
  title: Tom1, a VHS domain-containing protein, interacts with tollip, ubiquitin, and clathrin.
  findings: []
- id: PMID:15047686
  title: Tollip and Tom1 form a complex and recruit ubiquitin-conjugated proteins onto early
    endosomes.
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: PMID:16412388
  title: Recruitment of clathrin onto endosomes by the Tom1-Tollip complex.
  findings: []
- id: PMID:16713569
  title: A protein-protein interaction network for human inherited ataxias and disorders of Purkinje
    cell degeneration.
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:19060904
  title: An empirical framework for binary interactome mapping.
  findings: []
- id: PMID:19447967
  title: Shifted Transversal Design smart-pooling for high coverage interactome mapping.
  findings: []
- id: PMID:20936779
  title: A human MAP kinase interactome.
  findings: []
- id: PMID:21492153
  title: Analysis of proteomic changes induced upon cellular differentiation of the human intestinal
    cell line Caco-2.
  findings: []
- id: PMID:21903422
  title: Mapping a dynamic innate immunity protein interaction network regulating type I interferon
    production.
  findings: []
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in
    urine.
  findings: []
- id: PMID:25042851
  title: Autophagic clearance of polyQ proteins mediated by ubiquitin-Atg8 adaptors of the conserved
    CUET protein family.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings: []
- id: PMID:26320582
  title: Tom1 Modulates Binding of Tollip to Phosphatidylinositol 3-Phosphate via a Coupled Folding
    and Binding Mechanism.
  findings: []
- id: PMID:27107014
  title: An inter-species protein-protein interaction network across vast evolutionary distance.
  findings: []
- id: PMID:27368102
  title: An ER-Associated Pathway Defines Endosomal Architecture for Controlled Cargo Transport.
  findings: []
- id: PMID:31263572
  title: Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease.
  findings: []
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the allele
    frequency spectrum in human populations.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers
    Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:34524948
  title: Global Proximity Interactome of the Human Macroautophagy Pathway.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: Reactome:R-HSA-446634
  title: IRAK4 is activated by autophosphorylation
  findings: []
- id: Reactome:R-HSA-446684
  title: IRAK2 is phosphorylated downstream of IRAK4 following IL1 receptor activation
  findings: []
- id: Reactome:R-HSA-446692
  title: IRAK1 binds to MYD88 within the IL1R complex
  findings: []
- id: Reactome:R-HSA-446694
  title: IRAK4 phosphorylates IRAK1
  findings: []
- id: Reactome:R-HSA-446701
  title: IRAK4-activated IRAK1 autophosphorylates
  findings: []
- id: Reactome:R-HSA-446862
  title: Hyperphosphorylated IRAK1 associates with TRAF6
  findings: []
- id: Reactome:R-HSA-446868
  title: The Interleukin 1 receptor complex binds Tollip
  findings: []
- id: Reactome:R-HSA-446894
  title: TRAF6 binding leads to IRAK1:TRAF6 release
  findings: []
- id: Reactome:R-HSA-6798749
  title: Exocytosis of specific granule lumen proteins
  findings: []
- id: Reactome:R-HSA-6798751
  title: Exocytosis of azurophil granule lumen proteins
  findings: []
- id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
  title: Falcon deep research synthesis for TOLLIP
  findings: []
core_functions:
- description: Ubiquitin- and phosphoinositide-directed molecular adaptor activity that routes
    ubiquitinated or aberrant membrane cargo toward endolysosomal degradation.
  molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  directly_involved_in:
  - id: GO:0036010
    label: protein localization to endosome
  - id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  locations:
  - id: GO:0005768
    label: endosome
  - id: GO:0005769
    label: early endosome
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
    supporting_text: 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/IL‑1R pathways) and (ii)
      **sorting/trafficking of ubiquitinated or aberrant proteins toward endolysosomal degradation**
  - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
    supporting_text: '**C2 domain (~central ~130 aa)**: binds **phosphoinositides**; in a 2023 mechanistic
      study, the C2 domain showed preferential interaction with **PI3P** and **PI(4,5)P2**, consistent
      with **membrane/endosome targeting** and PI3P-vesicle coupling'
  - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
    supporting_text: '**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'
- description: CUE-domain ubiquitin-conjugate binding that supports cargo selection and
    receptor-proximal signaling complex regulation.
  molecular_function:
    id: GO:0043130
    label: ubiquitin binding
  directly_involved_in:
  - id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  - id: GO:0070498
    label: interleukin-1-mediated signaling pathway
  - id: GO:0045087
    label: innate immune response
  locations:
  - id: GO:0005768
    label: endosome
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
    supporting_text: '**CUE domain (C-terminal; mapped as aa 231–274)**: 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)'
  - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
    supporting_text: '**TLR/IL‑1R → Myddosome/IRAK1 → NF‑κB**: TOLLIP restrains IRAK1 in resting cells;
      BLK-mediated phosphorylation on Y76/Y86/Y152 releases IRAK1 for hyperphosphorylation and stronger
      NF‑κB signaling'
  - reference_id: file:human/TOLLIP/TOLLIP-deep-research-falcon.md
    supporting_text: 'TOLLIP is a **non-enzymatic adaptor** whose primary biochemical capabilities are
      **specific binding interactions**:'
proposed_new_terms: []
suggested_questions: []
suggested_experiments: []

Gene Description

Existing Annotations Review

Core Functions

Ubiquitin- and phosphoinositide-directed molecular adaptor activity that routes ubiquitinated or aberrant membrane cargo toward endolysosomal degradation.

CUE-domain ubiquitin-conjugate binding that supports cargo selection and receptor-proximal signaling complex regulation.

References

Deep Research

Falcon

Research report: Human TOLLIP (UniProt Q9H0E2) functional annotation

0) Target verification (mandatory)

1) Key concepts and definitions (current understanding)

1.1 What TOLLIP is

1.2 Domain architecture and domain-defined functions

1.3 Cellular localization

2) Recent developments and latest research (prioritizing 2023–2024)

2.1 (Dec 2023) A phosphorylation “switch” that converts TOLLIP from a brake to a permissive factor for TLR/IL‑1R signaling

2.2 (Nov 2023) TOLLIP as a cargo adaptor for selective lysosomal degradation of aberrant ER membrane proteins

2.3 (Feb 2024) Expert synthesis: TOLLIP as a “multitasking” adaptor coordinating negative regulation and trafficking

3) Current applications and real-world implementations

3.1 Clinical trial implementation: genotyping TOLLIP SNPs as a candidate modifier of N-acetylcysteine (NAC) response

3.2 Translational disease associations (target–disease knowledgebases)

4) Expert opinions and analysis (authoritative sources)

4.1 Consensus view: adaptor integrating ubiquitin, membranes, and receptor signaling

4.2 Updated 2023–2024 perspective: “negative regulator” is accurate but incomplete

5) Relevant statistics and data points from recent studies

5.1 Quantitative trafficking readouts (Hayashi et al., EMBO J 2023)

5.2 Sample sizes and quantitative design features (Li et al., JCB 2023)

5.3 Quantitative association signals (Open Targets snapshot)

Mechanistic functional annotation summary (human TOLLIP/Q9H0E2)

Primary molecular function

Cellular sites of action

Major pathways

Key 2023–2024 references (URLs and dates)

Notable evidence gaps (based on retrieved sources)

Citations

📄 View Raw YAML