{"gene":"TOLLIP","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2000,"finding":"Tollip is present in a complex with IRAK before IL-1β treatment; upon IL-1β stimulation, Tollip-IRAK complexes are recruited to the activated receptor complex through direct association of Tollip with IL-1RAcP; co-recruited MyD88 then triggers IRAK autophosphorylation, leading to dissociation of IRAK from Tollip; overexpression of Tollip impairs NF-κB activation.","method":"Co-immunoprecipitation, overexpression in cell lines, NF-κB reporter assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing protein complex membership, functional NF-κB reporter assay, widely replicated across subsequent studies","pmids":["10854325"],"is_preprint":false},{"year":2001,"finding":"Tollip directly associates with TLR2 and TLR4; Tollip potently suppresses IRAK kinase activity after TLR activation; Tollip is itself phosphorylated by IRAK upon LPS or IL-1 stimulation, establishing it as a bona fide IRAK substrate; Tollip plays an inhibitory role in TLR-mediated NF-κB activation.","method":"Co-immunoprecipitation, in vitro kinase assay, NF-κB reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay demonstrating IRAK-dependent phosphorylation, Co-IP for TLR2/4 binding, replicated by multiple groups","pmids":["11751856"],"is_preprint":false},{"year":2003,"finding":"Tom1 binds directly to ubiquitin chains and to Tollip; endogenous Tom1 associates with Tollip to form a stable complex as shown by gel filtration and Western blot; Tom1 also binds clathrin heavy chain through a clathrin-binding motif, and the Tom1-Tollip complex is proposed to link polyubiquitinated proteins to clathrin.","method":"Direct binding assays, gel filtration, co-immunoprecipitation, fluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, gel filtration of endogenous complex, confirmed by two independent groups (PMIDs 14563850 and 15047686)","pmids":["14563850"],"is_preprint":false},{"year":2004,"finding":"Tom1 GAT domain interacts with ubiquitin and Tollip in a mutually exclusive manner; Tollip localizes on early endosomes and recruits Tom1 and ubiquitinated proteins to endosomes; Tollip and Tom1 form a complex that regulates endosomal trafficking of ubiquitinated proteins.","method":"Co-immunoprecipitation, GST pulldown, subcellular localization by fluorescence microscopy, mutational analysis of GAT domain","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, localization experiments with functional context, replicated independently","pmids":["15047686"],"is_preprint":false},{"year":2004,"finding":"Tollip preferentially binds phosphatidylinositol-3-phosphate (PtdIns(3)P) and PtdIns(3,4,5)P3 in vitro via its C2 domain; mutation of lysine 150 to glutamic acid (K150E) in the C2 domain abolishes phosphoinositide binding and eliminates Tollip's ability to inhibit LPS-induced NF-κB reporter activity; Tollip-mediated inhibition of NF-κB can be alleviated by the PI3K inhibitor wortmannin.","method":"Lipid-binding assay in vitro, site-directed mutagenesis, NF-κB reporter assay, pharmacological inhibition","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro lipid binding assay combined with mutagenesis and functional NF-κB reporter, single lab with multiple orthogonal methods","pmids":["15140579"],"is_preprint":false},{"year":2006,"finding":"Tom1 family proteins (Tom1, Tom1L1, Tom1L2) interact with Tollip via their GAT domains; when co-expressed with Tollip, all Tom1 family proteins recruit clathrin onto early endosomes, indicating Tom1 family proteins modulate endosomal function in conjunction with Tollip.","method":"Co-immunoprecipitation, subcellular localization by fluorescence microscopy","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and localization, replicated across Tom1 family members within single study","pmids":["16412388"],"is_preprint":false},{"year":2006,"finding":"IL-1β induces ubiquitination of IL-1RI; ubiquitinated IL-1RI interacts with Tollip; Tollip is required for sorting of IL-1RI at late endosomes for lysosomal degradation; in Tollip-deficient cells or cells expressing ubiquitin/IL-1RI-binding-deficient Tollip mutants, IL-1RI accumulates on late endosomes and is not efficiently degraded; Tom1 also interacts with IL-1RI and its knockdown similarly causes IL-1RI accumulation at late endosomes.","method":"Ubiquitination assay, IL-1RI trafficking assay, Tollip-deficient cells, mutant Tollip expression, Tom1 siRNA knockdown","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function (KO cells and mutants) with defined trafficking phenotype, multiple orthogonal approaches in one study","pmids":["17113392"],"is_preprint":false},{"year":2006,"finding":"Tollip-deficient mice show normal NF-κB and MAPK signaling upon IL-1β or LPS stimulation, but produce significantly reduced proinflammatory cytokines IL-6 and TNF-α at low but not high doses of IL-1β or LPS; Tollip controls the magnitude of inflammatory cytokine production rather than the activation state of signaling kinases.","method":"Tollip knockout mouse, cytokine ELISA, NF-κB and MAPK signaling assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with well-defined cellular phenotype, contrasting with prior in vitro overexpression studies","pmids":["16428431"],"is_preprint":false},{"year":2007,"finding":"The death domain of IRAK-1 mediates its interactions with Tollip, MyD88, and IRAK-4; mutation of threonine 66 in the IRAK-1 death domain (T66A or T66D) stabilizes binding to Tollip (and MyD88, IRAK-4), confirming these interactions are mediated by the IRAK-1 death domain.","method":"Co-immunoprecipitation, site-directed mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with Co-IP, single lab","pmids":["17276401"],"is_preprint":false},{"year":2009,"finding":"Tollip interacts with SUMO-1 and sumoylation enzymes including Daxx as identified by yeast two-hybrid and confirmed by GST pulldown and co-immunoprecipitation; Tollip mediates sumoylation of the TIR domain of the IL-1RI cytoplasmic region; Tollip co-localizes with SUMO-1 and Daxx in nuclear bodies.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunofluorescence","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast two-hybrid confirmed by GST pulldown and Co-IP, single lab","pmids":["19198660"],"is_preprint":false},{"year":2009,"finding":"DSCR1-1S (Down syndrome candidate region 1) interacts with Tollip and causes dissociation of IRAK-1 from Tollip; both DSCR1-1S and Tollip interact with TRAF6, and DSCR1-1S reduces the Tollip-TRAF6 interaction; DSCR1-1S stimulates IL-1R-mediated NF-κB activation and IL-8 production downstream of Tollip modulation.","method":"Co-immunoprecipitation, NF-κB reporter assay, IL-8 ELISA","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for protein interactions with functional reporter assay, single lab","pmids":["19716405"],"is_preprint":false},{"year":2010,"finding":"The Tollip CUE domain forms a stable dimer as determined by size-exclusion chromatography and crosslinking; NMR backbone assignment reveals three helical elements comprising 52% of the CUE domain backbone; circular dichroism confirms helical nature.","method":"NMR spectroscopy, size-exclusion chromatography, molecular crosslinking, circular dichroism","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR structural characterization, single lab, no mutagenesis-based functional validation in this paper","pmids":["20957454"],"is_preprint":false},{"year":2011,"finding":"The Tollip C2 domain preferentially binds PtdIns3P and PtdIns(4,5)P2 in a Ca2+-independent manner with low micromolar affinity; NMR analysis shows PtdIns3P and PtdIns(4,5)P2 share overlapping binding residues; mutational analysis identifies conserved basic residues required for phosphoinositide binding; the C2 domain binds Ca2+ which may be required for membrane targeting.","method":"NMR spectroscopy, lipid-protein overlay assay, kinetic binding studies, site-directed mutagenesis","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR with mutagenesis and kinetic binding studies, multiple orthogonal methods, single lab","pmids":["21294713"],"is_preprint":false},{"year":2011,"finding":"Tollip co-localizes with and stimulates aggregation of polyglutamine-expanded huntingtin via its ubiquitin-binding function; Tollip overexpression protects cells against polyQ-expanded htt toxicity, proposed to occur by sequestration of toxic species into inclusions.","method":"Co-localization by fluorescence microscopy, cell viability assay, overexpression in HD cell model","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — fluorescence co-localization and cell viability assay, single lab, multiple readouts","pmids":["21896309"],"is_preprint":false},{"year":2011,"finding":"Transcription factor Elf-1 negatively regulates Tollip gene expression by binding its proximal promoter; in intestinal epithelial cells, insufficient O-GlcNAc modification of Elf-1 prevents its nuclear translocation, thereby relieving Elf-1-mediated repression and elevating Tollip transcription.","method":"Reporter gene assay, ChIP, O-GlcNAc modification analysis, nuclear/cytoplasm fractionation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay with ChIP and fractionation, single lab, multiple methods","pmids":["21867680"],"is_preprint":false},{"year":2012,"finding":"PINK1 specifically binds both Tollip and IRAK1; upon IL-1β stimulation, PINK1 association with Tollip increases, facilitating dissociation of Tollip from IRAK1 and assembly of the IRAK1-TRAF6 complex; PINK1 enhances K63-linked polyubiquitination of IRAK1 and increases NF-κB activity, overcoming Tollip's inhibitory action.","method":"Co-immunoprecipitation, ubiquitination assay, NF-κB reporter assay, PINK1 knockout MEFs","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with KO cells and ubiquitination assay, single lab","pmids":["23244239"],"is_preprint":false},{"year":2012,"finding":"TOLLIP knockdown in human monocytes suppresses TNF and IL-6 production after TLR2 and TLR4 ligand stimulation and induces IL-10 secretion, demonstrating that TOLLIP has an anti-inflammatory effect on TLR signaling in human primary cells.","method":"shRNA knockdown in peripheral blood human monocytes, cytokine ELISA","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown in primary human cells with cytokine readout, single lab","pmids":["22778396"],"is_preprint":false},{"year":2012,"finding":"Tollip interacts with Smad7 and with ubiquitinated TGF-β type I receptor (TβRI); Smad7 enhances Tollip-TβRI interaction and colocalization; Tollip overexpression accelerates degradation of activated TβRI by altering its endosomal trafficking; Tollip overexpression antagonizes TGF-β transcriptional responses, Smad2 phosphorylation, and epithelial-mesenchymal transition.","method":"Co-immunoprecipitation, subcellular localization/colocalization microscopy, protein degradation assay, Smad2 phosphorylation, reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional trafficking and signaling readouts, single lab, multiple methods","pmids":["23027871"],"is_preprint":false},{"year":2013,"finding":"Ubiquitin binds both the C2 domain and CUE domain of Tollip at overlapping sites; ubiquitin binding to the C2 domain inhibits PtdIns3P binding; NMR shows the C2 and CUE domains bind overlapping sites on ubiquitin suggesting two ubiquitin molecules associate simultaneously; ubiquitin binding disrupts the dimeric state of the CUE domain.","method":"NMR spectroscopy, hydrodynamic studies, lipid-binding assay, mutational analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR with hydrodynamic studies and lipid competition assays, multiple orthogonal methods, single lab","pmids":["23880770"],"is_preprint":false},{"year":2013,"finding":"Tollip overexpression in cardiac myocytes significantly attenuates IL-1β-induced hypertrophic response (reduced cell size, decreased ANP expression) by reducing NF-κB binding activity and phospho-p38; in vivo, TAC reduces Tollip-IRAK-1 association and increases NF-κB activity.","method":"Cardiac myocyte transfection/overexpression, TAC mouse model, NF-κB EMSA, co-immunoprecipitation","journal":"Frontiers in bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with functional hypertrophy readout combined with in vivo model and Co-IP, single lab","pmids":["19273233"],"is_preprint":false},{"year":2013,"finding":"Tollip transgenic mice with cardiac-specific overexpression show attenuated aortic banding-induced cardiac hypertrophy, fibrosis, and dysfunction; global Tollip knockout mice show aggravated hypertrophy; mechanistically, Tollip interacts with AKT and suppresses its downstream signaling; pre-activation of AKT largely offsets Tollip's anti-hypertrophic effects.","method":"Transgenic and knockout mouse models, aortic banding, co-immunoprecipitation, rescue experiment with AKT activation","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — both gain- and loss-of-function mouse models with defined phenotype, Co-IP for AKT interaction, epistasis rescue experiment","pmids":["24285748"],"is_preprint":false},{"year":2013,"finding":"Tollip overexpression antagonizes MARCH1 function; Tollip reduces MARCH1 protein levels; Tollip and MARCH1 compete for binding to MHC class II molecules; Tollip knockdown in CIITA+ HeLa cells increases HLA-DR expression and reduces MHC II-CLIP association.","method":"siRNA knockdown, co-immunoprecipitation, protein expression analysis, flow cytometry","journal":"Results in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP and expression data with limited functional mechanistic follow-up","pmids":["24600555"],"is_preprint":false},{"year":2015,"finding":"Ezh1 suppresses Tollip gene transcription by directly binding the proximal Tollip promoter and maintaining high levels of H3K27me3 there; Ezh1 silencing upregulates Tollip, and Tollip silencing rescues TLR-triggered cytokine production in Ezh1-silenced macrophages, placing Ezh1 upstream of Tollip in a regulatory axis.","method":"ChIP, transcriptome analysis, siRNA knockdown, cytokine assays, rescue experiment","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter H3K27me3, combined with epistasis rescue experiment, single lab with multiple orthogonal methods","pmids":["25687760"],"is_preprint":false},{"year":2015,"finding":"Tollip inhibits canonical Wnt signaling; depletion of Tollip potentiates β-catenin/TCF-dependent transcriptional reporter activity while overexpression inhibits it; Tollip counteracts β-catenin nuclear accumulation without affecting its total levels; the ubiquitin-binding CUE domain is required for this effect; Wnt regulation by Tollip is independent of dynamin-mediated endocytosis; this is conserved in zebrafish early embryonic development.","method":"RNAi screen, β-catenin/TCF reporter assay, overexpression, domain mutant analysis, zebrafish in vivo","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays, domain mutagenesis, and in vivo zebrafish validation, single lab","pmids":["26110841"],"is_preprint":false},{"year":2015,"finding":"Tollip deficiency protects mice against cerebral ischemia-reperfusion injury by attenuating neuronal apoptosis and inflammation; Tollip overexpression exacerbates injury; mechanistically, Tollip suppresses Akt signaling, and its detrimental effects are largely mediated through Akt suppression.","method":"Knockout and transgenic mouse models, CRISPR-Cas9 knockout rat, neuron-specific overexpression, Akt signaling analysis","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic models (KO mouse, KO rat, OE mice) with consistent phenotype, mechanistic Akt link identified, single lab","pmids":["26011492"],"is_preprint":false},{"year":2017,"finding":"Tollip deficiency in ApoE-/- mice compromises lipophagy, as shown by impaired fusion of lipid droplets with lysosomes in macrophages and hepatocytes by electron microscopy; elevated p62 levels and reduced Rab7 and GABARAP in Tollip-deficient tissues confirm disrupted lysosome fusion; Tollip deficiency leads to lipid accumulation and enlarged atherosclerotic plaques.","method":"Electron microscopy, Western blot (p62, Rab7, GABARAP), double-KO mouse model","journal":"Journal of the American Heart Association","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electron microscopy of lysosome-lipid droplet fusion with molecular markers, in vivo genetic model, single lab","pmids":["28396568"],"is_preprint":false},{"year":2019,"finding":"Tollip interacts with ASK1 and facilitates recruitment of TRAF6 to ASK1, promoting ASK1 N-terminal dimerization and activation of downstream MAPK (JNK/p38) signaling; the Tollip methionine and phenylalanine motif and TRAF6 ubiquitinating activity are required for this Tollip-regulated ASK1-MAPK axis; Tollip deficiency reduces hepatic ischemia-reperfusion injury.","method":"Co-immunoprecipitation, site-directed mutagenesis, knockout mouse, proteomic analysis, MAPK signaling assays","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis identifying required motifs, supported by KO mouse model, single lab","pmids":["31077413"],"is_preprint":false},{"year":2019,"finding":"Tollip deficiency leads to enhanced tumor immune surveillance; Tollip-deficient neutrophils show elevated CD80 (costimulatory) and reduced PD-L1 (inhibitory) expression; mechanistically, Tollip deficiency increases STAT5 and reduces STAT1; adoptive transfer of Tollip-deficient neutrophils (but not monocytes) is sufficient to drive enhanced anti-tumor immunity in vivo.","method":"Knockout mouse, chemically induced colorectal cancer model, flow cytometry, adoptive transfer, Western blot for STAT1/STAT5","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — adoptive transfer providing functional demonstration, combined with molecular mechanism (STAT1/5), single lab","pmids":["30674719"],"is_preprint":false},{"year":2020,"finding":"TOLLIP directly interacts with STING at the resting state to prevent its degradation; Tollip deficiency results in reduced STING protein in nonhematopoietic and immune cells; the competing degradation mechanism requires IRE1α and lysosomes; polyQ proteins in Huntington's disease sequester TOLLIP away from STING, leading to reduced STING protein and dampened immune signaling; Tollip-/- ameliorates STING-mediated autoimmune disease in Trex1-/- mice.","method":"Co-immunoprecipitation, knockout mice, Trex1-/- cross, protein stability assays, Huntington's disease mouse model","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction demonstrated by Co-IP, multiple genetic models, disease-relevant in vivo contexts, published in high-tier journal","pmids":["31932809"],"is_preprint":false},{"year":2020,"finding":"Tollip interacts with Parkin via its CUE domain in a Tom1-independent and mitophagy-independent manner; the interaction requires Parkin's intact UBL domain but is independent of Parkin's mitochondrial recruitment and E3 ligase activity; Tollip regulates Parkin-dependent endosomal trafficking of TOM20-positive mitochondrial-derived vesicles (MDVs) to lysosomes; this requires Tollip's ubiquitin-binding, endosomal membrane interaction, and Tom1 interaction.","method":"Co-immunoprecipitation, domain mutagenesis, MDV trafficking assay, Tollip KO cells, retromer inhibition","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain dissection by mutagenesis with Co-IP, functional MDV trafficking assay in KO cells, multiple orthogonal approaches","pmids":["32311122"],"is_preprint":false},{"year":2020,"finding":"Tollip functions as a bacterial autophagy receptor for group A Streptococcus (GAS); Tollip is recruited to GAS-containing endosomal vacuoles; Tollip KO disrupts recruitment of NBR1, TAX1BP1, and NDP52 to GAS-containing autophagosomes; Tollip interacts with galectin-7 (by co-immunoprecipitation) and recruits galectin-1 and -7 to GAS autophagosomes; galectin-1 and -7 restrict GAS replication.","method":"Tollip KO cells, fluorescence microscopy, co-immunoprecipitation, bacterial survival assay","journal":"Frontiers in cellular and infection microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cells with defined autophagy phenotype and Co-IP of galectin-7 interaction, single lab","pmids":["33425778"],"is_preprint":false},{"year":2022,"finding":"TOLLIP acts as a cargo receptor for selective autophagic degradation of CGAS; viral UL21 scaffolds E3 ligase UBE3C to catalyze K27-linked ubiquitination of CGAS at Lys384; this ubiquitin mark is recognized by TOLLIP, targeting CGAS for lysosomal degradation.","method":"Co-immunoprecipitation, ubiquitination assay (K27-linked), CRISPR knockout, autophagy inhibitor experiments","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP combined with specific ubiquitin linkage assay and CRISPR KO, single lab","pmids":["36343628"],"is_preprint":false},{"year":2022,"finding":"Prevention of ACE2 SUMOylation at K187 promotes K48-linked ubiquitination of ACE2, which leads to TOLLIP-dependent autophagic degradation of ACE2; TOLLIP deficiency stabilizes ACE2 and elevates SARS-CoV-2 infection.","method":"Co-immunoprecipitation, ubiquitination assay, TOLLIP knockdown/knockout, ACE2 stability assay, SARS-CoV-2 infection assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic link between SUMOylation, ubiquitination, and TOLLIP-dependent degradation demonstrated by multiple biochemical methods, single lab","pmids":["36057605"],"is_preprint":false},{"year":2023,"finding":"TOLLIP promotes selective lysosomal degradation of aberrant ER membrane proteins (including motoneuron disease-causing VAPB and Seipin mutants) through its PI3P-binding and ubiquitin-binding CUE domain; TOLLIP recognizes misfolded cargo via an intrinsically disordered region (IDR); TOLLIP depletion augments ER stress after ERAD inhibition, indicating cooperative roles of TOLLIP and ERAD in ER proteostasis.","method":"TOLLIP depletion, lysosomal degradation assays, domain mutant analysis (IDR and CUE), ER stress assay, PI3P binding","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mutagenesis (IDR and CUE) combined with functional degradation assays and ER stress epistasis, multiple orthogonal methods in a rigorous study","pmids":["37929762"],"is_preprint":false},{"year":2023,"finding":"RNF167 interacts with Tollip through Tollip's CUE domain and functions as the E3 ligase attaching K33-linked polyubiquitin chains to Tollip at Lys235; Tollip inhibits TNF-α-induced NF-κB and MAPK activation, and the K235R mutation on Tollip abolishes this inhibitory effect.","method":"Co-immunoprecipitation, ubiquitination assay (K33-linked), site-directed mutagenesis (K235R), NF-κB/MAPK signaling assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with specific ubiquitin linkage assay and mutagenesis-based functional validation, single lab","pmids":["37410058"],"is_preprint":false},{"year":2025,"finding":"TOLLIP forms condensates via its intrinsically disordered region (IDR); these condensates interact with SENP1, promote its aggregation, and enhance SENP1-MAVS interaction, leading to deSUMOylation and reduced aggregation of MAVS; TOLLIP deficiency leads to enhanced type I interferon responses upon RNA viral infection; Tollip-/- mice are more resistant to lethal VSV infection.","method":"Phase separation/condensate assay, Co-immunoprecipitation, TOLLIP KO mice, VSV infection model, SUMO assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — condensate formation assay with Co-IP and in vivo KO mouse validation, single lab","pmids":["40022729"],"is_preprint":false},{"year":2005,"finding":"Tollip and IRAK-1 are identified as caveolin-1-interacting proteins in monocytes; following CD26 stimulation, Tollip and IRAK-1 dissociate from caveolin-1, IRAK-1 becomes phosphorylated in the cytosol, and NF-κB is activated, leading to upregulation of CD86.","method":"Proteomic analysis, co-immunoprecipitation, Western blot for phospho-IRAK-1","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — proteomic identification confirmed by Co-IP, functional NF-κB readout, single lab","pmids":["16107720"],"is_preprint":false},{"year":2011,"finding":"E. coli CNF1 toxin promotes Rac1-dependent bacterial entry; Tollip is a new interacting protein of Rac1 and ubiquitinated Rac1; Tollip knockdown reduces CNF1-induced Rac1-dependent UPEC entry and Listeria monocytogenes entry; Tollip, Tom1, and clathrin associate with Rac1 and localize at sites of bacterial entry.","method":"Co-immunoprecipitation, siRNA knockdown, bacterial entry assay, fluorescence microscopy","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with bacterial entry phenotype plus Co-IP for Rac1 interaction, single lab","pmids":["21291504"],"is_preprint":false},{"year":2022,"finding":"Tollip interacts with STAT3; Tollip-deficient human airway epithelial cells show higher STAT3 activation and eotaxin-3 production after IL-13 stimulation; a STAT3 inhibitor reduces excessive eotaxin-3 in Tollip-deficient cells, placing STAT3 downstream of Tollip in IL-13 signaling.","method":"Co-immunoprecipitation, siRNA knockdown, STAT3 pharmacological inhibition, ELISA","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for Tollip-STAT3 interaction combined with knockdown and rescue pharmacology, single lab","pmids":["35172835"],"is_preprint":false},{"year":2018,"finding":"Tollip negatively regulates vascular smooth muscle cell (VSMC) proliferation, dedifferentiation, and migration; Tollip overexpression exerts protective effects against neointima formation by suppressing Akt-dependent signaling; Tollip deficiency exaggerates neointima formation; an Akt-specific inhibitor confirms the Akt-dependence of Tollip's protective role.","method":"Tollip KO mouse model of vascular injury, VSMC overexpression and knockdown, neointima histology, Akt inhibitor rescue","journal":"Journal of the American Heart Association","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with gain/loss-of-function in VSMCs, pharmacological rescue epistasis, single lab","pmids":["29887521"],"is_preprint":false}],"current_model":"TOLLIP is a multifunctional adaptor protein that: (1) negatively regulates IL-1R/TLR signaling by binding IL-1RAcP and holding IRAK in an inactive complex, acting as an IRAK substrate upon stimulation, and suppressing IRAK kinase activity; (2) localizes to early endosomes via its C2 domain by binding PtdIns3P, where it recruits Tom1 and clathrin to direct ubiquitinated cargo (including IL-1RI, TβRI, and ACE2) toward lysosomal degradation; (3) stabilizes resting-state STING by direct interaction, counterbalancing IRE1α/lysosome-mediated STING degradation; (4) coordinates Parkin-dependent mitochondrial-derived vesicle trafficking to lysosomes via its ubiquitin-binding CUE domain; (5) promotes selective autophagic degradation of aberrant ER membrane proteins and acts as a cargo receptor for bacterial autophagy; (6) suppresses AKT and STAT3 signaling in cardiovascular and airway inflammatory contexts; (7) forms IDR-dependent condensates that enhance SENP1-mediated deSUMOylation of MAVS to dampen antiviral RLR signaling; and (8) is itself post-translationally regulated by RNF167-mediated K33-linked ubiquitination at K235 and by Ezh1-mediated H3K27me3 at its promoter."},"narrative":{"mechanistic_narrative":"TOLLIP is a multifunctional ubiquitin- and phosphoinositide-binding adaptor that tunes innate immune signaling and routes ubiquitinated cargo through endosomal and autophagic degradation [PMID:10854325, PMID:17113392, PMID:32311122]. In the IL-1R/TLR pathway it sits in a preformed complex with IRAK, is recruited to the activated receptor through direct binding to IL-1RAcP, becomes an IRAK substrate upon stimulation, and suppresses IRAK kinase activity to restrain NF-κB activation [PMID:10854325, PMID:11751856]; genetic loss in mice shows it sets the magnitude of low-dose cytokine output rather than the on/off state of signaling kinases [PMID:16428431], an anti-inflammatory role confirmed in human monocytes [PMID:22778396]. Membrane and cargo targeting is built from defined domains: a C2 domain binds PtdIns3P to localize TOLLIP to early endosomes [PMID:15140579, PMID:21294713], while ubiquitin engages overlapping sites on both the C2 and the dimeric CUE domain, with ubiquitin binding competing with phosphoinositide engagement [PMID:20957454, PMID:23880770]. Through a stable complex with Tom1 (which also binds clathrin), TOLLIP sorts ubiquitinated receptors—including IL-1RI and the activated TGF-β type I receptor—toward lysosomal degradation [PMID:14563850, PMID:15047686, PMID:17113392, PMID:23027871]. The same ubiquitin-recognition machinery underlies its activity as a selective autophagy and degradation receptor: it routes Parkin-dependent mitochondrial-derived vesicles to lysosomes via its CUE domain [PMID:32311122], degrades aberrant ER membrane proteins through cooperating IDR and CUE domains [PMID:37929762], and acts as a cargo receptor that recognizes specifically ubiquitinated CGAS and ACE2 for autophagic destruction [PMID:36343628, PMID:36057605]. TOLLIP also stabilizes resting-state STING by direct interaction, counterbalancing IRE1α/lysosome-dependent STING turnover [PMID:31932809], and forms IDR-dependent condensates that recruit SENP1 to deSUMOylate MAVS and dampen RLR antiviral signaling [PMID:40022729]. In cardiovascular, neuronal, and airway contexts it acts as a brake on AKT and STAT3 signaling [PMID:24285748, PMID:26011492, PMID:35172835]. TOLLIP expression is repressed by Ezh1-mediated H3K27me3 at its promoter [PMID:25687760], and the protein is modified by RNF167-catalyzed K33-linked ubiquitination at Lys235 that is required for its inhibition of TNF-α-induced signaling [PMID:37410058].","teleology":[{"year":2000,"claim":"Established TOLLIP's founding function: how IL-1R signaling is held in check, by showing TOLLIP pre-associates with IRAK and is delivered to the receptor via IL-1RAcP where IRAK is then activated and dissociates.","evidence":"Co-IP, overexpression and NF-κB reporter assays in cell lines","pmids":["10854325"],"confidence":"High","gaps":["Stoichiometry and structure of the resting TOLLIP-IRAK complex not defined","Endogenous physiological relevance addressed only later by KO"]},{"year":2001,"claim":"Extended the inhibitory role to TLR signaling and defined TOLLIP as a bona fide IRAK substrate that suppresses IRAK kinase activity.","evidence":"Co-IP for TLR2/4 binding, in vitro kinase assay, NF-κB reporter","pmids":["11751856"],"confidence":"High","gaps":["Phosphosites on TOLLIP and their functional consequence not mapped","Mechanism of kinase suppression undefined"]},{"year":2003,"claim":"Linked TOLLIP to ubiquitin-dependent trafficking by identifying its stable complex with Tom1, which bridges polyubiquitinated cargo to clathrin.","evidence":"Direct binding, gel filtration of endogenous complex, Co-IP, microscopy","pmids":["14563850"],"confidence":"High","gaps":["Cargo identity not yet defined","In vivo trafficking consequence not shown"]},{"year":2004,"claim":"Defined the membrane-targeting mechanism: the C2 domain binds PtdIns3P, localizing TOLLIP to early endosomes where it recruits Tom1 and ubiquitinated cargo.","evidence":"Lipid-binding assay, K150E mutagenesis, NF-κB reporter, wortmannin; GAT-domain mapping and localization","pmids":["15140579","15047686"],"confidence":"High","gaps":["Ca2+ requirement for membrane targeting not fully resolved","How lipid binding integrates with signaling inhibition unclear"]},{"year":2006,"claim":"Provided in vivo trafficking and signaling resolution: TOLLIP sorts ubiquitinated IL-1RI to lysosomes, while KO mice revealed it sets cytokine magnitude at low ligand doses rather than gating kinase activation.","evidence":"Ubiquitination/trafficking assays in TOLLIP-deficient and mutant cells; TOLLIP KO mouse with cytokine ELISA and signaling assays","pmids":["17113392","16428431"],"confidence":"High","gaps":["Reconciliation of overexpression inhibition versus modest KO phenotype incomplete","Dose-dependence mechanism not defined"]},{"year":2010,"claim":"Structurally characterized the ubiquitin-binding module by showing the CUE domain is a helical dimer.","evidence":"NMR, size-exclusion chromatography, crosslinking, circular dichroism","pmids":["20957454"],"confidence":"Medium","gaps":["No mutagenesis-based functional validation in this study","Dimer relevance to cargo recognition not yet tested"]},{"year":2011,"claim":"Refined the lipid-binding interface, showing the C2 domain binds PtdIns3P/PtdIns(4,5)P2 in a Ca2+-independent manner via conserved basic residues.","evidence":"NMR, lipid-overlay, kinetic binding, site-directed mutagenesis","pmids":["21294713"],"confidence":"High","gaps":["Physiological lipid preference in cells not directly demonstrated"]},{"year":2012,"claim":"Broadened TOLLIP's receptor-degradation role beyond immune receptors, showing Smad7-assisted targeting of ubiquitinated TβRI for endosomal degradation and antagonism of TGF-β responses.","evidence":"Co-IP, colocalization microscopy, degradation/Smad2 phosphorylation/reporter assays","pmids":["23027871"],"confidence":"Medium","gaps":["Largely overexpression-based","Endogenous contribution to TGF-β signaling not established"]},{"year":2013,"claim":"Resolved how lipid and ubiquitin binding are coordinated: ubiquitin binds overlapping sites on the C2 and CUE domains, competes with PtdIns3P, and disrupts CUE dimerization, implying a regulatory switch.","evidence":"NMR, hydrodynamic studies, lipid-competition assays, mutagenesis","pmids":["23880770"],"confidence":"High","gaps":["Cellular consequence of the lipid/ubiquitin switch not directly tested","Linkage-type selectivity of ubiquitin recognition unresolved"]},{"year":2013,"claim":"Identified an AKT-suppressing function in cardiac protection using complementary gain- and loss-of-function mouse models.","evidence":"Cardiac-specific transgenic and global KO mice, aortic banding, Co-IP, AKT pre-activation rescue","pmids":["24285748"],"confidence":"High","gaps":["Direct mechanism of AKT suppression undefined","Whether ubiquitin/lipid binding is required not tested"]},{"year":2015,"claim":"Placed TOLLIP within an epigenetic regulatory axis, showing Ezh1-deposited H3K27me3 represses its promoter to control TLR-triggered cytokine output.","evidence":"ChIP, transcriptome, siRNA, cytokine assays, epistasis rescue","pmids":["25687760"],"confidence":"High","gaps":["Upstream signals controlling Ezh1 at the promoter not defined"]},{"year":2017,"claim":"Connected TOLLIP to lysosomal degradation of lipid droplets, showing deficiency impairs lipophagy and worsens atherosclerosis.","evidence":"Electron microscopy, Western blot for autophagy markers, double-KO mice","pmids":["28396568"],"confidence":"Medium","gaps":["Molecular cargo recognition step in lipophagy not defined"]},{"year":2020,"claim":"Defined TOLLIP as a stabilizer of resting STING, counterbalancing IRE1α/lysosome-mediated turnover, and showed polyQ proteins sequester it to dampen STING signaling.","evidence":"Co-IP, KO mice, Trex1-/- cross, protein-stability assays, HD mouse model","pmids":["31932809"],"confidence":"High","gaps":["Structural basis of TOLLIP-STING interaction unknown","How TOLLIP shields STING from degradation mechanistically unclear"]},{"year":2020,"claim":"Demonstrated that the CUE domain mediates Parkin binding to route mitochondrial-derived vesicles to lysosomes, independent of canonical mitophagy.","evidence":"Co-IP, domain mutagenesis, MDV trafficking assay in KO cells, retromer inhibition","pmids":["32311122"],"confidence":"High","gaps":["Ubiquitin signal on MDV cargo recognized by TOLLIP not defined","Relationship to PINK1 not addressed here"]},{"year":2020,"claim":"Established TOLLIP as a bacterial autophagy receptor for group A Streptococcus that organizes recruitment of autophagy receptors and restrictive galectins.","evidence":"TOLLIP KO cells, microscopy, Co-IP of galectin-7, bacterial survival assay","pmids":["33425778"],"confidence":"Medium","gaps":["Direct ubiquitin/cargo signal recognized on GAS vacuoles not mapped"]},{"year":2022,"claim":"Generalized the cargo-receptor model to selective autophagic degradation of CGAS and ACE2 marked by specific ubiquitin linkages, linking TOLLIP to antiviral and SARS-CoV-2-relevant turnover.","evidence":"Co-IP, K27/K48-linked ubiquitination assays, CRISPR KO, degradation and SARS-CoV-2 infection assays","pmids":["36343628","36057605"],"confidence":"Medium","gaps":["Which TOLLIP domain reads each linkage type not fully resolved","In vivo relevance of ACE2 degradation untested"]},{"year":2023,"claim":"Showed TOLLIP degrades aberrant ER membrane proteins via cooperating IDR (misfolded-cargo recognition) and CUE/PI3P-binding domains, defining a lysosomal arm of ER proteostasis cooperating with ERAD.","evidence":"Depletion, lysosomal degradation assays, IDR and CUE mutants, ER stress epistasis, PI3P binding","pmids":["37929762"],"confidence":"High","gaps":["How the IDR distinguishes misfolded substrates unclear"]},{"year":2023,"claim":"Identified post-translational control of TOLLIP itself: RNF167 attaches K33-linked ubiquitin at Lys235, a modification required for TOLLIP to inhibit TNF-α-induced NF-κB/MAPK signaling.","evidence":"Co-IP, K33-linked ubiquitination assay, K235R mutagenesis, signaling assays","pmids":["37410058"],"confidence":"Medium","gaps":["How K33 ubiquitination alters TOLLIP activity mechanistically unknown"]},{"year":2025,"claim":"Revealed a condensate-based mechanism whereby TOLLIP IDR-driven phase separation recruits SENP1 to deSUMOylate MAVS, dampening RLR antiviral responses.","evidence":"Condensate assays, Co-IP, SUMO assays, TOLLIP KO mice, VSV infection model","pmids":["40022729"],"confidence":"Medium","gaps":["In vivo requirement for condensate formation not isolated from other TOLLIP functions"]},{"year":null,"claim":"How TOLLIP's distinct domains and condensate behavior are switched among its many roles—signaling brake, endosomal sorter, autophagy receptor, and protein stabilizer—within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model coordinating C2/CUE/IDR engagement across pathways","Linkage-type code for ubiquitin recognition incompletely defined","Determinants selecting degradation versus stabilization of bound partners unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,3,6]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4,12]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[31,32,33,30]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,7]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3,4,6,29]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[6,25,29,33]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune 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Inhibits cell activation by microbial products. Recruits IRAK1 to the IL-1 receptor complex (PubMed:10854325). Inhibits IRAK1 phosphorylation and kinase activity (PubMed:11751856). Connects the ubiquitin pathway to autophagy by functioning as a ubiquitin-ATG8 family adapter and thus mediating autophagic clearance of ubiquitin conjugates (PubMed:25042851). The TOLLIP-dependent selective autophagy pathway plays an important role in clearance of cytotoxic polyQ proteins aggregates (PubMed:25042851). In a complex with TOM1, recruits ubiquitin-conjugated proteins onto early endosomes (PubMed:15047686). Binds to phosphatidylinositol 3-phosphate (PtdIns(3)P) (PubMed:26320582)","subcellular_location":"Cytoplasm; Endosome; Early endosome","url":"https://www.uniprot.org/uniprotkb/Q9H0E2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TOLLIP","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000078902","cell_line_id":"CID001853","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"TOM1L1","stoichiometry":10.0},{"gene":"TOM1","stoichiometry":4.0},{"gene":"MYO6","stoichiometry":0.2},{"gene":"CLTC","stoichiometry":0.2},{"gene":"TOM1L2","stoichiometry":0.2},{"gene":"KIAA0368;ECM29","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001853","total_profiled":1310},"omim":[{"mim_id":"619510","title":"IMMUNODEFICIENCY 85 AND AUTOIMMUNITY; IMD85","url":"https://www.omim.org/entry/619510"},{"mim_id":"615519","title":"TARGET OF MYB1-LIKE 2 MEMBRANE TRAFFICKING PROTEIN; TOM1L2","url":"https://www.omim.org/entry/615519"},{"mim_id":"607948","title":"MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/607948"},{"mim_id":"606277","title":"TOLL-INTERACTING PROTEIN; TOLLIP","url":"https://www.omim.org/entry/606277"},{"mim_id":"604701","title":"TARGET OF MYB1-LIKE 1 MEMBRANE TRAFFICKING PROTEIN; TOM1L1","url":"https://www.omim.org/entry/604701"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Primary cilium tip","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TOLLIP"},"hgnc":{"alias_symbol":["IL-1RAcPIP"],"prev_symbol":[]},"alphafold":{"accession":"Q9H0E2","domains":[{"cath_id":"2.60.40.150","chopping":"51-177","consensus_level":"high","plddt":95.1643,"start":51,"end":177},{"cath_id":"1.10.8.10","chopping":"231-270","consensus_level":"high","plddt":84.4078,"start":231,"end":270}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0E2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0E2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0E2-F1-predicted_aligned_error_v6.png","plddt_mean":80.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TOLLIP","jax_strain_url":"https://www.jax.org/strain/search?query=TOLLIP"},"sequence":{"accession":"Q9H0E2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H0E2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H0E2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0E2"}},"corpus_meta":[{"pmid":"11751856","id":"PMC_11751856","title":"Negative 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IRAK-1.","date":"2019","source":"American journal of physiology. 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upon IL-1β stimulation, Tollip-IRAK complexes are recruited to the activated receptor complex through direct association of Tollip with IL-1RAcP; co-recruited MyD88 then triggers IRAK autophosphorylation, leading to dissociation of IRAK from Tollip; overexpression of Tollip impairs NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression in cell lines, NF-κB reporter assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing protein complex membership, functional NF-κB reporter assay, widely replicated across subsequent studies\",\n      \"pmids\": [\"10854325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Tollip directly associates with TLR2 and TLR4; Tollip potently suppresses IRAK kinase activity after TLR activation; Tollip is itself phosphorylated by IRAK upon LPS or IL-1 stimulation, establishing it as a bona fide IRAK substrate; Tollip plays an inhibitory role in TLR-mediated NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, NF-κB reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay demonstrating IRAK-dependent phosphorylation, Co-IP for TLR2/4 binding, replicated by multiple groups\",\n      \"pmids\": [\"11751856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Tom1 binds directly to ubiquitin chains and to Tollip; endogenous Tom1 associates with Tollip to form a stable complex as shown by gel filtration and Western blot; Tom1 also binds clathrin heavy chain through a clathrin-binding motif, and the Tom1-Tollip complex is proposed to link polyubiquitinated proteins to clathrin.\",\n      \"method\": \"Direct binding assays, gel filtration, co-immunoprecipitation, fluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, gel filtration of endogenous complex, confirmed by two independent groups (PMIDs 14563850 and 15047686)\",\n      \"pmids\": [\"14563850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Tom1 GAT domain interacts with ubiquitin and Tollip in a mutually exclusive manner; Tollip localizes on early endosomes and recruits Tom1 and ubiquitinated proteins to endosomes; Tollip and Tom1 form a complex that regulates endosomal trafficking of ubiquitinated proteins.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, subcellular localization by fluorescence microscopy, mutational analysis of GAT domain\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, localization experiments with functional context, replicated independently\",\n      \"pmids\": [\"15047686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Tollip preferentially binds phosphatidylinositol-3-phosphate (PtdIns(3)P) and PtdIns(3,4,5)P3 in vitro via its C2 domain; mutation of lysine 150 to glutamic acid (K150E) in the C2 domain abolishes phosphoinositide binding and eliminates Tollip's ability to inhibit LPS-induced NF-κB reporter activity; Tollip-mediated inhibition of NF-κB can be alleviated by the PI3K inhibitor wortmannin.\",\n      \"method\": \"Lipid-binding assay in vitro, site-directed mutagenesis, NF-κB reporter assay, pharmacological inhibition\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro lipid binding assay combined with mutagenesis and functional NF-κB reporter, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15140579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Tom1 family proteins (Tom1, Tom1L1, Tom1L2) interact with Tollip via their GAT domains; when co-expressed with Tollip, all Tom1 family proteins recruit clathrin onto early endosomes, indicating Tom1 family proteins modulate endosomal function in conjunction with Tollip.\",\n      \"method\": \"Co-immunoprecipitation, subcellular localization by fluorescence microscopy\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and localization, replicated across Tom1 family members within single study\",\n      \"pmids\": [\"16412388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-1β induces ubiquitination of IL-1RI; ubiquitinated IL-1RI interacts with Tollip; Tollip is required for sorting of IL-1RI at late endosomes for lysosomal degradation; in Tollip-deficient cells or cells expressing ubiquitin/IL-1RI-binding-deficient Tollip mutants, IL-1RI accumulates on late endosomes and is not efficiently degraded; Tom1 also interacts with IL-1RI and its knockdown similarly causes IL-1RI accumulation at late endosomes.\",\n      \"method\": \"Ubiquitination assay, IL-1RI trafficking assay, Tollip-deficient cells, mutant Tollip expression, Tom1 siRNA knockdown\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function (KO cells and mutants) with defined trafficking phenotype, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"17113392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Tollip-deficient mice show normal NF-κB and MAPK signaling upon IL-1β or LPS stimulation, but produce significantly reduced proinflammatory cytokines IL-6 and TNF-α at low but not high doses of IL-1β or LPS; Tollip controls the magnitude of inflammatory cytokine production rather than the activation state of signaling kinases.\",\n      \"method\": \"Tollip knockout mouse, cytokine ELISA, NF-κB and MAPK signaling assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with well-defined cellular phenotype, contrasting with prior in vitro overexpression studies\",\n      \"pmids\": [\"16428431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The death domain of IRAK-1 mediates its interactions with Tollip, MyD88, and IRAK-4; mutation of threonine 66 in the IRAK-1 death domain (T66A or T66D) stabilizes binding to Tollip (and MyD88, IRAK-4), confirming these interactions are mediated by the IRAK-1 death domain.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with Co-IP, single lab\",\n      \"pmids\": [\"17276401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Tollip interacts with SUMO-1 and sumoylation enzymes including Daxx as identified by yeast two-hybrid and confirmed by GST pulldown and co-immunoprecipitation; Tollip mediates sumoylation of the TIR domain of the IL-1RI cytoplasmic region; Tollip co-localizes with SUMO-1 and Daxx in nuclear bodies.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast two-hybrid confirmed by GST pulldown and Co-IP, single lab\",\n      \"pmids\": [\"19198660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DSCR1-1S (Down syndrome candidate region 1) interacts with Tollip and causes dissociation of IRAK-1 from Tollip; both DSCR1-1S and Tollip interact with TRAF6, and DSCR1-1S reduces the Tollip-TRAF6 interaction; DSCR1-1S stimulates IL-1R-mediated NF-κB activation and IL-8 production downstream of Tollip modulation.\",\n      \"method\": \"Co-immunoprecipitation, NF-κB reporter assay, IL-8 ELISA\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for protein interactions with functional reporter assay, single lab\",\n      \"pmids\": [\"19716405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The Tollip CUE domain forms a stable dimer as determined by size-exclusion chromatography and crosslinking; NMR backbone assignment reveals three helical elements comprising 52% of the CUE domain backbone; circular dichroism confirms helical nature.\",\n      \"method\": \"NMR spectroscopy, size-exclusion chromatography, molecular crosslinking, circular dichroism\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR structural characterization, single lab, no mutagenesis-based functional validation in this paper\",\n      \"pmids\": [\"20957454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The Tollip C2 domain preferentially binds PtdIns3P and PtdIns(4,5)P2 in a Ca2+-independent manner with low micromolar affinity; NMR analysis shows PtdIns3P and PtdIns(4,5)P2 share overlapping binding residues; mutational analysis identifies conserved basic residues required for phosphoinositide binding; the C2 domain binds Ca2+ which may be required for membrane targeting.\",\n      \"method\": \"NMR spectroscopy, lipid-protein overlay assay, kinetic binding studies, site-directed mutagenesis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR with mutagenesis and kinetic binding studies, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"21294713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Tollip co-localizes with and stimulates aggregation of polyglutamine-expanded huntingtin via its ubiquitin-binding function; Tollip overexpression protects cells against polyQ-expanded htt toxicity, proposed to occur by sequestration of toxic species into inclusions.\",\n      \"method\": \"Co-localization by fluorescence microscopy, cell viability assay, overexpression in HD cell model\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — fluorescence co-localization and cell viability assay, single lab, multiple readouts\",\n      \"pmids\": [\"21896309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Transcription factor Elf-1 negatively regulates Tollip gene expression by binding its proximal promoter; in intestinal epithelial cells, insufficient O-GlcNAc modification of Elf-1 prevents its nuclear translocation, thereby relieving Elf-1-mediated repression and elevating Tollip transcription.\",\n      \"method\": \"Reporter gene assay, ChIP, O-GlcNAc modification analysis, nuclear/cytoplasm fractionation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay with ChIP and fractionation, single lab, multiple methods\",\n      \"pmids\": [\"21867680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PINK1 specifically binds both Tollip and IRAK1; upon IL-1β stimulation, PINK1 association with Tollip increases, facilitating dissociation of Tollip from IRAK1 and assembly of the IRAK1-TRAF6 complex; PINK1 enhances K63-linked polyubiquitination of IRAK1 and increases NF-κB activity, overcoming Tollip's inhibitory action.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, NF-κB reporter assay, PINK1 knockout MEFs\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with KO cells and ubiquitination assay, single lab\",\n      \"pmids\": [\"23244239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TOLLIP knockdown in human monocytes suppresses TNF and IL-6 production after TLR2 and TLR4 ligand stimulation and induces IL-10 secretion, demonstrating that TOLLIP has an anti-inflammatory effect on TLR signaling in human primary cells.\",\n      \"method\": \"shRNA knockdown in peripheral blood human monocytes, cytokine ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown in primary human cells with cytokine readout, single lab\",\n      \"pmids\": [\"22778396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Tollip interacts with Smad7 and with ubiquitinated TGF-β type I receptor (TβRI); Smad7 enhances Tollip-TβRI interaction and colocalization; Tollip overexpression accelerates degradation of activated TβRI by altering its endosomal trafficking; Tollip overexpression antagonizes TGF-β transcriptional responses, Smad2 phosphorylation, and epithelial-mesenchymal transition.\",\n      \"method\": \"Co-immunoprecipitation, subcellular localization/colocalization microscopy, protein degradation assay, Smad2 phosphorylation, reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional trafficking and signaling readouts, single lab, multiple methods\",\n      \"pmids\": [\"23027871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Ubiquitin binds both the C2 domain and CUE domain of Tollip at overlapping sites; ubiquitin binding to the C2 domain inhibits PtdIns3P binding; NMR shows the C2 and CUE domains bind overlapping sites on ubiquitin suggesting two ubiquitin molecules associate simultaneously; ubiquitin binding disrupts the dimeric state of the CUE domain.\",\n      \"method\": \"NMR spectroscopy, hydrodynamic studies, lipid-binding assay, mutational analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR with hydrodynamic studies and lipid competition assays, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"23880770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tollip overexpression in cardiac myocytes significantly attenuates IL-1β-induced hypertrophic response (reduced cell size, decreased ANP expression) by reducing NF-κB binding activity and phospho-p38; in vivo, TAC reduces Tollip-IRAK-1 association and increases NF-κB activity.\",\n      \"method\": \"Cardiac myocyte transfection/overexpression, TAC mouse model, NF-κB EMSA, co-immunoprecipitation\",\n      \"journal\": \"Frontiers in bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with functional hypertrophy readout combined with in vivo model and Co-IP, single lab\",\n      \"pmids\": [\"19273233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tollip transgenic mice with cardiac-specific overexpression show attenuated aortic banding-induced cardiac hypertrophy, fibrosis, and dysfunction; global Tollip knockout mice show aggravated hypertrophy; mechanistically, Tollip interacts with AKT and suppresses its downstream signaling; pre-activation of AKT largely offsets Tollip's anti-hypertrophic effects.\",\n      \"method\": \"Transgenic and knockout mouse models, aortic banding, co-immunoprecipitation, rescue experiment with AKT activation\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — both gain- and loss-of-function mouse models with defined phenotype, Co-IP for AKT interaction, epistasis rescue experiment\",\n      \"pmids\": [\"24285748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tollip overexpression antagonizes MARCH1 function; Tollip reduces MARCH1 protein levels; Tollip and MARCH1 compete for binding to MHC class II molecules; Tollip knockdown in CIITA+ HeLa cells increases HLA-DR expression and reduces MHC II-CLIP association.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, protein expression analysis, flow cytometry\",\n      \"journal\": \"Results in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP and expression data with limited functional mechanistic follow-up\",\n      \"pmids\": [\"24600555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ezh1 suppresses Tollip gene transcription by directly binding the proximal Tollip promoter and maintaining high levels of H3K27me3 there; Ezh1 silencing upregulates Tollip, and Tollip silencing rescues TLR-triggered cytokine production in Ezh1-silenced macrophages, placing Ezh1 upstream of Tollip in a regulatory axis.\",\n      \"method\": \"ChIP, transcriptome analysis, siRNA knockdown, cytokine assays, rescue experiment\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter H3K27me3, combined with epistasis rescue experiment, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25687760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Tollip inhibits canonical Wnt signaling; depletion of Tollip potentiates β-catenin/TCF-dependent transcriptional reporter activity while overexpression inhibits it; Tollip counteracts β-catenin nuclear accumulation without affecting its total levels; the ubiquitin-binding CUE domain is required for this effect; Wnt regulation by Tollip is independent of dynamin-mediated endocytosis; this is conserved in zebrafish early embryonic development.\",\n      \"method\": \"RNAi screen, β-catenin/TCF reporter assay, overexpression, domain mutant analysis, zebrafish in vivo\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays, domain mutagenesis, and in vivo zebrafish validation, single lab\",\n      \"pmids\": [\"26110841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Tollip deficiency protects mice against cerebral ischemia-reperfusion injury by attenuating neuronal apoptosis and inflammation; Tollip overexpression exacerbates injury; mechanistically, Tollip suppresses Akt signaling, and its detrimental effects are largely mediated through Akt suppression.\",\n      \"method\": \"Knockout and transgenic mouse models, CRISPR-Cas9 knockout rat, neuron-specific overexpression, Akt signaling analysis\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic models (KO mouse, KO rat, OE mice) with consistent phenotype, mechanistic Akt link identified, single lab\",\n      \"pmids\": [\"26011492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Tollip deficiency in ApoE-/- mice compromises lipophagy, as shown by impaired fusion of lipid droplets with lysosomes in macrophages and hepatocytes by electron microscopy; elevated p62 levels and reduced Rab7 and GABARAP in Tollip-deficient tissues confirm disrupted lysosome fusion; Tollip deficiency leads to lipid accumulation and enlarged atherosclerotic plaques.\",\n      \"method\": \"Electron microscopy, Western blot (p62, Rab7, GABARAP), double-KO mouse model\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electron microscopy of lysosome-lipid droplet fusion with molecular markers, in vivo genetic model, single lab\",\n      \"pmids\": [\"28396568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tollip interacts with ASK1 and facilitates recruitment of TRAF6 to ASK1, promoting ASK1 N-terminal dimerization and activation of downstream MAPK (JNK/p38) signaling; the Tollip methionine and phenylalanine motif and TRAF6 ubiquitinating activity are required for this Tollip-regulated ASK1-MAPK axis; Tollip deficiency reduces hepatic ischemia-reperfusion injury.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, knockout mouse, proteomic analysis, MAPK signaling assays\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis identifying required motifs, supported by KO mouse model, single lab\",\n      \"pmids\": [\"31077413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tollip deficiency leads to enhanced tumor immune surveillance; Tollip-deficient neutrophils show elevated CD80 (costimulatory) and reduced PD-L1 (inhibitory) expression; mechanistically, Tollip deficiency increases STAT5 and reduces STAT1; adoptive transfer of Tollip-deficient neutrophils (but not monocytes) is sufficient to drive enhanced anti-tumor immunity in vivo.\",\n      \"method\": \"Knockout mouse, chemically induced colorectal cancer model, flow cytometry, adoptive transfer, Western blot for STAT1/STAT5\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — adoptive transfer providing functional demonstration, combined with molecular mechanism (STAT1/5), single lab\",\n      \"pmids\": [\"30674719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TOLLIP directly interacts with STING at the resting state to prevent its degradation; Tollip deficiency results in reduced STING protein in nonhematopoietic and immune cells; the competing degradation mechanism requires IRE1α and lysosomes; polyQ proteins in Huntington's disease sequester TOLLIP away from STING, leading to reduced STING protein and dampened immune signaling; Tollip-/- ameliorates STING-mediated autoimmune disease in Trex1-/- mice.\",\n      \"method\": \"Co-immunoprecipitation, knockout mice, Trex1-/- cross, protein stability assays, Huntington's disease mouse model\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction demonstrated by Co-IP, multiple genetic models, disease-relevant in vivo contexts, published in high-tier journal\",\n      \"pmids\": [\"31932809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Tollip interacts with Parkin via its CUE domain in a Tom1-independent and mitophagy-independent manner; the interaction requires Parkin's intact UBL domain but is independent of Parkin's mitochondrial recruitment and E3 ligase activity; Tollip regulates Parkin-dependent endosomal trafficking of TOM20-positive mitochondrial-derived vesicles (MDVs) to lysosomes; this requires Tollip's ubiquitin-binding, endosomal membrane interaction, and Tom1 interaction.\",\n      \"method\": \"Co-immunoprecipitation, domain mutagenesis, MDV trafficking assay, Tollip KO cells, retromer inhibition\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain dissection by mutagenesis with Co-IP, functional MDV trafficking assay in KO cells, multiple orthogonal approaches\",\n      \"pmids\": [\"32311122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Tollip functions as a bacterial autophagy receptor for group A Streptococcus (GAS); Tollip is recruited to GAS-containing endosomal vacuoles; Tollip KO disrupts recruitment of NBR1, TAX1BP1, and NDP52 to GAS-containing autophagosomes; Tollip interacts with galectin-7 (by co-immunoprecipitation) and recruits galectin-1 and -7 to GAS autophagosomes; galectin-1 and -7 restrict GAS replication.\",\n      \"method\": \"Tollip KO cells, fluorescence microscopy, co-immunoprecipitation, bacterial survival assay\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells with defined autophagy phenotype and Co-IP of galectin-7 interaction, single lab\",\n      \"pmids\": [\"33425778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TOLLIP acts as a cargo receptor for selective autophagic degradation of CGAS; viral UL21 scaffolds E3 ligase UBE3C to catalyze K27-linked ubiquitination of CGAS at Lys384; this ubiquitin mark is recognized by TOLLIP, targeting CGAS for lysosomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K27-linked), CRISPR knockout, autophagy inhibitor experiments\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP combined with specific ubiquitin linkage assay and CRISPR KO, single lab\",\n      \"pmids\": [\"36343628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Prevention of ACE2 SUMOylation at K187 promotes K48-linked ubiquitination of ACE2, which leads to TOLLIP-dependent autophagic degradation of ACE2; TOLLIP deficiency stabilizes ACE2 and elevates SARS-CoV-2 infection.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, TOLLIP knockdown/knockout, ACE2 stability assay, SARS-CoV-2 infection assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic link between SUMOylation, ubiquitination, and TOLLIP-dependent degradation demonstrated by multiple biochemical methods, single lab\",\n      \"pmids\": [\"36057605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TOLLIP promotes selective lysosomal degradation of aberrant ER membrane proteins (including motoneuron disease-causing VAPB and Seipin mutants) through its PI3P-binding and ubiquitin-binding CUE domain; TOLLIP recognizes misfolded cargo via an intrinsically disordered region (IDR); TOLLIP depletion augments ER stress after ERAD inhibition, indicating cooperative roles of TOLLIP and ERAD in ER proteostasis.\",\n      \"method\": \"TOLLIP depletion, lysosomal degradation assays, domain mutant analysis (IDR and CUE), ER stress assay, PI3P binding\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mutagenesis (IDR and CUE) combined with functional degradation assays and ER stress epistasis, multiple orthogonal methods in a rigorous study\",\n      \"pmids\": [\"37929762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNF167 interacts with Tollip through Tollip's CUE domain and functions as the E3 ligase attaching K33-linked polyubiquitin chains to Tollip at Lys235; Tollip inhibits TNF-α-induced NF-κB and MAPK activation, and the K235R mutation on Tollip abolishes this inhibitory effect.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K33-linked), site-directed mutagenesis (K235R), NF-κB/MAPK signaling assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with specific ubiquitin linkage assay and mutagenesis-based functional validation, single lab\",\n      \"pmids\": [\"37410058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TOLLIP forms condensates via its intrinsically disordered region (IDR); these condensates interact with SENP1, promote its aggregation, and enhance SENP1-MAVS interaction, leading to deSUMOylation and reduced aggregation of MAVS; TOLLIP deficiency leads to enhanced type I interferon responses upon RNA viral infection; Tollip-/- mice are more resistant to lethal VSV infection.\",\n      \"method\": \"Phase separation/condensate assay, Co-immunoprecipitation, TOLLIP KO mice, VSV infection model, SUMO assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — condensate formation assay with Co-IP and in vivo KO mouse validation, single lab\",\n      \"pmids\": [\"40022729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Tollip and IRAK-1 are identified as caveolin-1-interacting proteins in monocytes; following CD26 stimulation, Tollip and IRAK-1 dissociate from caveolin-1, IRAK-1 becomes phosphorylated in the cytosol, and NF-κB is activated, leading to upregulation of CD86.\",\n      \"method\": \"Proteomic analysis, co-immunoprecipitation, Western blot for phospho-IRAK-1\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — proteomic identification confirmed by Co-IP, functional NF-κB readout, single lab\",\n      \"pmids\": [\"16107720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"E. coli CNF1 toxin promotes Rac1-dependent bacterial entry; Tollip is a new interacting protein of Rac1 and ubiquitinated Rac1; Tollip knockdown reduces CNF1-induced Rac1-dependent UPEC entry and Listeria monocytogenes entry; Tollip, Tom1, and clathrin associate with Rac1 and localize at sites of bacterial entry.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, bacterial entry assay, fluorescence microscopy\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with bacterial entry phenotype plus Co-IP for Rac1 interaction, single lab\",\n      \"pmids\": [\"21291504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Tollip interacts with STAT3; Tollip-deficient human airway epithelial cells show higher STAT3 activation and eotaxin-3 production after IL-13 stimulation; a STAT3 inhibitor reduces excessive eotaxin-3 in Tollip-deficient cells, placing STAT3 downstream of Tollip in IL-13 signaling.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, STAT3 pharmacological inhibition, ELISA\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for Tollip-STAT3 interaction combined with knockdown and rescue pharmacology, single lab\",\n      \"pmids\": [\"35172835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Tollip negatively regulates vascular smooth muscle cell (VSMC) proliferation, dedifferentiation, and migration; Tollip overexpression exerts protective effects against neointima formation by suppressing Akt-dependent signaling; Tollip deficiency exaggerates neointima formation; an Akt-specific inhibitor confirms the Akt-dependence of Tollip's protective role.\",\n      \"method\": \"Tollip KO mouse model of vascular injury, VSMC overexpression and knockdown, neointima histology, Akt inhibitor rescue\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with gain/loss-of-function in VSMCs, pharmacological rescue epistasis, single lab\",\n      \"pmids\": [\"29887521\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TOLLIP is a multifunctional adaptor protein that: (1) negatively regulates IL-1R/TLR signaling by binding IL-1RAcP and holding IRAK in an inactive complex, acting as an IRAK substrate upon stimulation, and suppressing IRAK kinase activity; (2) localizes to early endosomes via its C2 domain by binding PtdIns3P, where it recruits Tom1 and clathrin to direct ubiquitinated cargo (including IL-1RI, TβRI, and ACE2) toward lysosomal degradation; (3) stabilizes resting-state STING by direct interaction, counterbalancing IRE1α/lysosome-mediated STING degradation; (4) coordinates Parkin-dependent mitochondrial-derived vesicle trafficking to lysosomes via its ubiquitin-binding CUE domain; (5) promotes selective autophagic degradation of aberrant ER membrane proteins and acts as a cargo receptor for bacterial autophagy; (6) suppresses AKT and STAT3 signaling in cardiovascular and airway inflammatory contexts; (7) forms IDR-dependent condensates that enhance SENP1-mediated deSUMOylation of MAVS to dampen antiviral RLR signaling; and (8) is itself post-translationally regulated by RNF167-mediated K33-linked ubiquitination at K235 and by Ezh1-mediated H3K27me3 at its promoter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TOLLIP is a multifunctional ubiquitin- and phosphoinositide-binding adaptor that tunes innate immune signaling and routes ubiquitinated cargo through endosomal and autophagic degradation [#0, #6, #29]. In the IL-1R/TLR pathway it sits in a preformed complex with IRAK, is recruited to the activated receptor through direct binding to IL-1RAcP, becomes an IRAK substrate upon stimulation, and suppresses IRAK kinase activity to restrain NF-\\u03baB activation [#0, #1]; genetic loss in mice shows it sets the magnitude of low-dose cytokine output rather than the on/off state of signaling kinases [#7], an anti-inflammatory role confirmed in human monocytes [#16]. Membrane and cargo targeting is built from defined domains: a C2 domain binds PtdIns3P to localize TOLLIP to early endosomes [#4, #12], while ubiquitin engages overlapping sites on both the C2 and the dimeric CUE domain, with ubiquitin binding competing with phosphoinositide engagement [#11, #18]. Through a stable complex with Tom1 (which also binds clathrin), TOLLIP sorts ubiquitinated receptors\\u2014including IL-1RI and the activated TGF-\\u03b2 type I receptor\\u2014toward lysosomal degradation [#2, #3, #6, #17]. The same ubiquitin-recognition machinery underlies its activity as a selective autophagy and degradation receptor: it routes Parkin-dependent mitochondrial-derived vesicles to lysosomes via its CUE domain [#29], degrades aberrant ER membrane proteins through cooperating IDR and CUE domains [#33], and acts as a cargo receptor that recognizes specifically ubiquitinated CGAS and ACE2 for autophagic destruction [#31, #32]. TOLLIP also stabilizes resting-state STING by direct interaction, counterbalancing IRE1\\u03b1/lysosome-dependent STING turnover [#28], and forms IDR-dependent condensates that recruit SENP1 to deSUMOylate MAVS and dampen RLR antiviral signaling [#35]. In cardiovascular, neuronal, and airway contexts it acts as a brake on AKT and STAT3 signaling [#20, #24, #38]. TOLLIP expression is repressed by Ezh1-mediated H3K27me3 at its promoter [#22], and the protein is modified by RNF167-catalyzed K33-linked ubiquitination at Lys235 that is required for its inhibition of TNF-\\u03b1-induced signaling [#34].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established TOLLIP's founding function: how IL-1R signaling is held in check, by showing TOLLIP pre-associates with IRAK and is delivered to the receptor via IL-1RAcP where IRAK is then activated and dissociates.\",\n      \"evidence\": \"Co-IP, overexpression and NF-\\u03baB reporter assays in cell lines\",\n      \"pmids\": [\"10854325\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the resting TOLLIP-IRAK complex not defined\", \"Endogenous physiological relevance addressed only later by KO\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Extended the inhibitory role to TLR signaling and defined TOLLIP as a bona fide IRAK substrate that suppresses IRAK kinase activity.\",\n      \"evidence\": \"Co-IP for TLR2/4 binding, in vitro kinase assay, NF-\\u03baB reporter\",\n      \"pmids\": [\"11751856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosites on TOLLIP and their functional consequence not mapped\", \"Mechanism of kinase suppression undefined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linked TOLLIP to ubiquitin-dependent trafficking by identifying its stable complex with Tom1, which bridges polyubiquitinated cargo to clathrin.\",\n      \"evidence\": \"Direct binding, gel filtration of endogenous complex, Co-IP, microscopy\",\n      \"pmids\": [\"14563850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo identity not yet defined\", \"In vivo trafficking consequence not shown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the membrane-targeting mechanism: the C2 domain binds PtdIns3P, localizing TOLLIP to early endosomes where it recruits Tom1 and ubiquitinated cargo.\",\n      \"evidence\": \"Lipid-binding assay, K150E mutagenesis, NF-\\u03baB reporter, wortmannin; GAT-domain mapping and localization\",\n      \"pmids\": [\"15140579\", \"15047686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ca2+ requirement for membrane targeting not fully resolved\", \"How lipid binding integrates with signaling inhibition unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided in vivo trafficking and signaling resolution: TOLLIP sorts ubiquitinated IL-1RI to lysosomes, while KO mice revealed it sets cytokine magnitude at low ligand doses rather than gating kinase activation.\",\n      \"evidence\": \"Ubiquitination/trafficking assays in TOLLIP-deficient and mutant cells; TOLLIP KO mouse with cytokine ELISA and signaling assays\",\n      \"pmids\": [\"17113392\", \"16428431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of overexpression inhibition versus modest KO phenotype incomplete\", \"Dose-dependence mechanism not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Structurally characterized the ubiquitin-binding module by showing the CUE domain is a helical dimer.\",\n      \"evidence\": \"NMR, size-exclusion chromatography, crosslinking, circular dichroism\",\n      \"pmids\": [\"20957454\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis-based functional validation in this study\", \"Dimer relevance to cargo recognition not yet tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Refined the lipid-binding interface, showing the C2 domain binds PtdIns3P/PtdIns(4,5)P2 in a Ca2+-independent manner via conserved basic residues.\",\n      \"evidence\": \"NMR, lipid-overlay, kinetic binding, site-directed mutagenesis\",\n      \"pmids\": [\"21294713\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological lipid preference in cells not directly demonstrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Broadened TOLLIP's receptor-degradation role beyond immune receptors, showing Smad7-assisted targeting of ubiquitinated T\\u03b2RI for endosomal degradation and antagonism of TGF-\\u03b2 responses.\",\n      \"evidence\": \"Co-IP, colocalization microscopy, degradation/Smad2 phosphorylation/reporter assays\",\n      \"pmids\": [\"23027871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Largely overexpression-based\", \"Endogenous contribution to TGF-\\u03b2 signaling not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved how lipid and ubiquitin binding are coordinated: ubiquitin binds overlapping sites on the C2 and CUE domains, competes with PtdIns3P, and disrupts CUE dimerization, implying a regulatory switch.\",\n      \"evidence\": \"NMR, hydrodynamic studies, lipid-competition assays, mutagenesis\",\n      \"pmids\": [\"23880770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequence of the lipid/ubiquitin switch not directly tested\", \"Linkage-type selectivity of ubiquitin recognition unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified an AKT-suppressing function in cardiac protection using complementary gain- and loss-of-function mouse models.\",\n      \"evidence\": \"Cardiac-specific transgenic and global KO mice, aortic banding, Co-IP, AKT pre-activation rescue\",\n      \"pmids\": [\"24285748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism of AKT suppression undefined\", \"Whether ubiquitin/lipid binding is required not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed TOLLIP within an epigenetic regulatory axis, showing Ezh1-deposited H3K27me3 represses its promoter to control TLR-triggered cytokine output.\",\n      \"evidence\": \"ChIP, transcriptome, siRNA, cytokine assays, epistasis rescue\",\n      \"pmids\": [\"25687760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling Ezh1 at the promoter not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected TOLLIP to lysosomal degradation of lipid droplets, showing deficiency impairs lipophagy and worsens atherosclerosis.\",\n      \"evidence\": \"Electron microscopy, Western blot for autophagy markers, double-KO mice\",\n      \"pmids\": [\"28396568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular cargo recognition step in lipophagy not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined TOLLIP as a stabilizer of resting STING, counterbalancing IRE1\\u03b1/lysosome-mediated turnover, and showed polyQ proteins sequester it to dampen STING signaling.\",\n      \"evidence\": \"Co-IP, KO mice, Trex1-/- cross, protein-stability assays, HD mouse model\",\n      \"pmids\": [\"31932809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TOLLIP-STING interaction unknown\", \"How TOLLIP shields STING from degradation mechanistically unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that the CUE domain mediates Parkin binding to route mitochondrial-derived vesicles to lysosomes, independent of canonical mitophagy.\",\n      \"evidence\": \"Co-IP, domain mutagenesis, MDV trafficking assay in KO cells, retromer inhibition\",\n      \"pmids\": [\"32311122\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin signal on MDV cargo recognized by TOLLIP not defined\", \"Relationship to PINK1 not addressed here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established TOLLIP as a bacterial autophagy receptor for group A Streptococcus that organizes recruitment of autophagy receptors and restrictive galectins.\",\n      \"evidence\": \"TOLLIP KO cells, microscopy, Co-IP of galectin-7, bacterial survival assay\",\n      \"pmids\": [\"33425778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitin/cargo signal recognized on GAS vacuoles not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Generalized the cargo-receptor model to selective autophagic degradation of CGAS and ACE2 marked by specific ubiquitin linkages, linking TOLLIP to antiviral and SARS-CoV-2-relevant turnover.\",\n      \"evidence\": \"Co-IP, K27/K48-linked ubiquitination assays, CRISPR KO, degradation and SARS-CoV-2 infection assays\",\n      \"pmids\": [\"36343628\", \"36057605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which TOLLIP domain reads each linkage type not fully resolved\", \"In vivo relevance of ACE2 degradation untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed TOLLIP degrades aberrant ER membrane proteins via cooperating IDR (misfolded-cargo recognition) and CUE/PI3P-binding domains, defining a lysosomal arm of ER proteostasis cooperating with ERAD.\",\n      \"evidence\": \"Depletion, lysosomal degradation assays, IDR and CUE mutants, ER stress epistasis, PI3P binding\",\n      \"pmids\": [\"37929762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the IDR distinguishes misfolded substrates unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified post-translational control of TOLLIP itself: RNF167 attaches K33-linked ubiquitin at Lys235, a modification required for TOLLIP to inhibit TNF-\\u03b1-induced NF-\\u03baB/MAPK signaling.\",\n      \"evidence\": \"Co-IP, K33-linked ubiquitination assay, K235R mutagenesis, signaling assays\",\n      \"pmids\": [\"37410058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How K33 ubiquitination alters TOLLIP activity mechanistically unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a condensate-based mechanism whereby TOLLIP IDR-driven phase separation recruits SENP1 to deSUMOylate MAVS, dampening RLR antiviral responses.\",\n      \"evidence\": \"Condensate assays, Co-IP, SUMO assays, TOLLIP KO mice, VSV infection model\",\n      \"pmids\": [\"40022729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo requirement for condensate formation not isolated from other TOLLIP functions\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TOLLIP's distinct domains and condensate behavior are switched among its many roles\\u2014signaling brake, endosomal sorter, autophagy receptor, and protein stabilizer\\u2014within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model coordinating C2/CUE/IDR engagement across pathways\", \"Linkage-type code for ubiquitin recognition incompletely defined\", \"Determinants selecting degradation versus stabilization of bound partners unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0043130\", \"supporting_discovery_ids\": [18, 29, 33]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 3, 6]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4, 12]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [31, 32, 33, 30]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3, 4, 6, 29]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [6, 25, 29, 33]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 7, 28]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [25, 29, 31, 33]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 3, 6, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [20, 24, 38]}\n    ],\n    \"complexes\": [\"TOLLIP-Tom1 complex\", \"TOLLIP-IRAK complex\"],\n    \"partners\": [\"IRAK1\", \"TOM1\", \"IL1RAP\", \"STING1\", \"PARK2\", \"SENP1\", \"RNF167\", \"AKT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}