Affinage

TOLLIP

Toll-interacting protein · UniProt Q9H0E2

Length
274 aa
Mass
30.3 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2000 High

    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

    PMID:10854325

    Open questions at the time
    • Stoichiometry and structure of the resting TOLLIP-IRAK complex not defined
    • Endogenous physiological relevance addressed only later by KO
  2. 2001 High

    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

    PMID:11751856

    Open questions at the time
    • Phosphosites on TOLLIP and their functional consequence not mapped
    • Mechanism of kinase suppression undefined
  3. 2003 High

    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

    PMID:14563850

    Open questions at the time
    • Cargo identity not yet defined
    • In vivo trafficking consequence not shown
  4. 2004 High

    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

    PMID:15047686 PMID:15140579

    Open questions at the time
    • Ca2+ requirement for membrane targeting not fully resolved
    • How lipid binding integrates with signaling inhibition unclear
  5. 2006 High

    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

    PMID:16428431 PMID:17113392

    Open questions at the time
    • Reconciliation of overexpression inhibition versus modest KO phenotype incomplete
    • Dose-dependence mechanism not defined
  6. 2010 Medium

    Structurally characterized the ubiquitin-binding module by showing the CUE domain is a helical dimer.

    Evidence NMR, size-exclusion chromatography, crosslinking, circular dichroism

    PMID:20957454

    Open questions at the time
    • No mutagenesis-based functional validation in this study
    • Dimer relevance to cargo recognition not yet tested
  7. 2011 High

    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

    PMID:21294713

    Open questions at the time
    • Physiological lipid preference in cells not directly demonstrated
  8. 2012 Medium

    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

    PMID:23027871

    Open questions at the time
    • Largely overexpression-based
    • Endogenous contribution to TGF-β signaling not established
  9. 2013 High

    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

    PMID:23880770

    Open questions at the time
    • Cellular consequence of the lipid/ubiquitin switch not directly tested
    • Linkage-type selectivity of ubiquitin recognition unresolved
  10. 2013 High

    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

    PMID:24285748

    Open questions at the time
    • Direct mechanism of AKT suppression undefined
    • Whether ubiquitin/lipid binding is required not tested
  11. 2015 High

    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

    PMID:25687760

    Open questions at the time
    • Upstream signals controlling Ezh1 at the promoter not defined
  12. 2017 Medium

    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

    PMID:28396568

    Open questions at the time
    • Molecular cargo recognition step in lipophagy not defined
  13. 2020 High

    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

    PMID:31932809

    Open questions at the time
    • Structural basis of TOLLIP-STING interaction unknown
    • How TOLLIP shields STING from degradation mechanistically unclear
  14. 2020 High

    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

    PMID:32311122

    Open questions at the time
    • Ubiquitin signal on MDV cargo recognized by TOLLIP not defined
    • Relationship to PINK1 not addressed here
  15. 2020 Medium

    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

    PMID:33425778

    Open questions at the time
    • Direct ubiquitin/cargo signal recognized on GAS vacuoles not mapped
  16. 2022 Medium

    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

    PMID:36057605 PMID:36343628

    Open questions at the time
    • Which TOLLIP domain reads each linkage type not fully resolved
    • In vivo relevance of ACE2 degradation untested
  17. 2023 High

    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

    PMID:37929762

    Open questions at the time
    • How the IDR distinguishes misfolded substrates unclear
  18. 2023 Medium

    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

    PMID:37410058

    Open questions at the time
    • How K33 ubiquitination alters TOLLIP activity mechanistically unknown
  19. 2025 Medium

    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

    PMID:40022729

    Open questions at the time
    • In vivo requirement for condensate formation not isolated from other TOLLIP functions

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 4 GO:0060090 molecular adaptor activity 4 GO:0008289 lipid binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005764 lysosome 4 GO:0005768 endosome 4 GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-9612973 Autophagy 4 R-HSA-162582 Signal Transduction 3
Partners
AKT1IL1RAPIRAK1PARK2RNF167SENP1STING1TOM1
Complex memberships
TOLLIP-IRAK complexTOLLIP-Tom1 complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 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. Co-immunoprecipitation, overexpression in cell lines, NF-κB reporter assay Nature cell biology High 10854325
2001 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. Co-immunoprecipitation, in vitro kinase assay, NF-κB reporter assay The Journal of biological chemistry High 11751856
2003 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. Direct binding assays, gel filtration, co-immunoprecipitation, fluorescence microscopy The Journal of biological chemistry High 14563850
2004 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. Co-immunoprecipitation, GST pulldown, subcellular localization by fluorescence microscopy, mutational analysis of GAT domain The Journal of biological chemistry High 15047686
2004 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. Lipid-binding assay in vitro, site-directed mutagenesis, NF-κB reporter assay, pharmacological inhibition Molecular immunology High 15140579
2006 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. Co-immunoprecipitation, subcellular localization by fluorescence microscopy Biochemical and biophysical research communications Medium 16412388
2006 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. Ubiquitination assay, IL-1RI trafficking assay, Tollip-deficient cells, mutant Tollip expression, Tom1 siRNA knockdown Current biology : CB High 17113392
2006 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. Tollip knockout mouse, cytokine ELISA, NF-κB and MAPK signaling assays Molecular and cellular biology High 16428431
2007 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. Co-immunoprecipitation, site-directed mutagenesis Biochemical and biophysical research communications Medium 17276401
2009 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. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunofluorescence PloS one Medium 19198660
2009 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. Co-immunoprecipitation, NF-κB reporter assay, IL-8 ELISA Biochimica et biophysica acta Medium 19716405
2010 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. NMR spectroscopy, size-exclusion chromatography, molecular crosslinking, circular dichroism Molecules and cells Medium 20957454
2011 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. NMR spectroscopy, lipid-protein overlay assay, kinetic binding studies, site-directed mutagenesis The Biochemical journal High 21294713
2011 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. Co-localization by fluorescence microscopy, cell viability assay, overexpression in HD cell model Neuroscience letters Medium 21896309
2011 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. Reporter gene assay, ChIP, O-GlcNAc modification analysis, nuclear/cytoplasm fractionation Biochemical and biophysical research communications Medium 21867680
2012 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. Co-immunoprecipitation, ubiquitination assay, NF-κB reporter assay, PINK1 knockout MEFs Journal of neuroinflammation Medium 23244239
2012 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. shRNA knockdown in peripheral blood human monocytes, cytokine ELISA Journal of immunology Medium 22778396
2012 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. Co-immunoprecipitation, subcellular localization/colocalization microscopy, protein degradation assay, Smad2 phosphorylation, reporter assay The Journal of biological chemistry Medium 23027871
2013 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. NMR spectroscopy, hydrodynamic studies, lipid-binding assay, mutational analysis The Journal of biological chemistry High 23880770
2013 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. Cardiac myocyte transfection/overexpression, TAC mouse model, NF-κB EMSA, co-immunoprecipitation Frontiers in bioscience Medium 19273233
2013 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. Transgenic and knockout mouse models, aortic banding, co-immunoprecipitation, rescue experiment with AKT activation Cardiovascular research High 24285748
2013 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. siRNA knockdown, co-immunoprecipitation, protein expression analysis, flow cytometry Results in immunology Low 24600555
2015 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. ChIP, transcriptome analysis, siRNA knockdown, cytokine assays, rescue experiment Journal of immunology High 25687760
2015 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. RNAi screen, β-catenin/TCF reporter assay, overexpression, domain mutant analysis, zebrafish in vivo PloS one Medium 26110841
2015 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. Knockout and transgenic mouse models, CRISPR-Cas9 knockout rat, neuron-specific overexpression, Akt signaling analysis The Journal of pathology Medium 26011492
2017 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. Electron microscopy, Western blot (p62, Rab7, GABARAP), double-KO mouse model Journal of the American Heart Association Medium 28396568
2019 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. Co-immunoprecipitation, site-directed mutagenesis, knockout mouse, proteomic analysis, MAPK signaling assays Hepatology Medium 31077413
2019 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. Knockout mouse, chemically induced colorectal cancer model, flow cytometry, adoptive transfer, Western blot for STAT1/STAT5 JCI insight Medium 30674719
2020 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. Co-immunoprecipitation, knockout mice, Trex1-/- cross, protein stability assays, Huntington's disease mouse model Nature immunology High 31932809
2020 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. Co-immunoprecipitation, domain mutagenesis, MDV trafficking assay, Tollip KO cells, retromer inhibition The EMBO journal High 32311122
2020 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. Tollip KO cells, fluorescence microscopy, co-immunoprecipitation, bacterial survival assay Frontiers in cellular and infection microbiology Medium 33425778
2022 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. Co-immunoprecipitation, ubiquitination assay (K27-linked), CRISPR knockout, autophagy inhibitor experiments Autophagy Medium 36343628
2022 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. Co-immunoprecipitation, ubiquitination assay, TOLLIP knockdown/knockout, ACE2 stability assay, SARS-CoV-2 infection assay Nature communications Medium 36057605
2023 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. TOLLIP depletion, lysosomal degradation assays, domain mutant analysis (IDR and CUE), ER stress assay, PI3P binding The EMBO journal High 37929762
2023 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. Co-immunoprecipitation, ubiquitination assay (K33-linked), site-directed mutagenesis (K235R), NF-κB/MAPK signaling assay FASEB journal Medium 37410058
2025 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. Phase separation/condensate assay, Co-immunoprecipitation, TOLLIP KO mice, VSV infection model, SUMO assay Cell reports Medium 40022729
2005 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. Proteomic analysis, co-immunoprecipitation, Western blot for phospho-IRAK-1 Molecular and cellular biology Medium 16107720
2011 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. Co-immunoprecipitation, siRNA knockdown, bacterial entry assay, fluorescence microscopy Traffic Medium 21291504
2022 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. Co-immunoprecipitation, siRNA knockdown, STAT3 pharmacological inhibition, ELISA Respiratory research Medium 35172835
2018 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. Tollip KO mouse model of vascular injury, VSMC overexpression and knockdown, neointima histology, Akt inhibitor rescue Journal of the American Heart Association Medium 29887521

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Negative regulation of toll-like receptor-mediated signaling by Tollip. The Journal of biological chemistry 479 11751856
2000 Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nature cell biology 437 10854325
2015 TOLLIP, MUC5B, and the Response to N-Acetylcysteine among Individuals with Idiopathic Pulmonary Fibrosis. American journal of respiratory and critical care medicine 259 26331942
2006 Tollip regulates proinflammatory responses to interleukin-1 and lipopolysaccharide. Molecular and cellular biology 159 16428431
2004 Tollip and Tom1 form a complex and recruit ubiquitin-conjugated proteins onto early endosomes. The Journal of biological chemistry 129 15047686
2003 Tom1, a VHS domain-containing protein, interacts with tollip, ubiquitin, and clathrin. The Journal of biological chemistry 115 14563850
2006 Intracellular trafficking of interleukin-1 receptor I requires Tollip. Current biology : CB 113 17113392
2012 Human TOLLIP regulates TLR2 and TLR4 signaling and its polymorphisms are associated with susceptibility to tuberculosis. Journal of immunology (Baltimore, Md. : 1950) 111 22778396
2020 Homeostatic regulation of STING protein at the resting state by stabilizer TOLLIP. Nature immunology 109 31932809
2011 Tollip: a multitasking protein in innate immunity and protein trafficking. Microbes and infection 102 21930231
2020 Tollip coordinates Parkin-dependent trafficking of mitochondrial-derived vesicles. The EMBO journal 94 32311122
2004 Characterization of Tollip protein upon Lipopolysaccharide challenge. Molecular immunology 87 15140579
2022 Tegument protein UL21 of alpha-herpesvirus inhibits the innate immunity by triggering CGAS degradation through TOLLIP-mediated selective autophagy. Autophagy 76 36343628
2005 CD26 mediates dissociation of Tollip and IRAK-1 from caveolin-1 and induces upregulation of CD86 on antigen-presenting cells. Molecular and cellular biology 68 16107720
2012 Tollip, an intracellular trafficking protein, is a novel modulator of the transforming growth factor-β signaling pathway. The Journal of biological chemistry 67 23027871
2015 Differential expression of key regulators of Toll-like receptors in ulcerative colitis and Crohn's disease: a role for Tollip and peroxisome proliferator-activated receptor gamma? Clinical and experimental immunology 57 26462859
2022 Suppression of ACE2 SUMOylation protects against SARS-CoV-2 infection through TOLLIP-mediated selective autophagy. Nature communications 54 36057605
2017 Bifidobacterium adolescentis protects against necrotizing enterocolitis and upregulates TOLLIP and SIGIRR in premature neonatal rats. BMC pediatrics 54 28056921
2019 Integrated Omics Reveals Tollip as an Regulator and Therapeutic Target for Hepatic Ischemia-Reperfusion Injury in Mice. Hepatology (Baltimore, Md.) 53 31077413
2023 African Swine Fever Virus L83L Negatively Regulates the cGAS-STING-Mediated IFN-I Pathway by Recruiting Tollip To Promote STING Autophagic Degradation. Journal of virology 50 36779759
2006 Recruitment of clathrin onto endosomes by the Tom1-Tollip complex. Biochemical and biophysical research communications 50 16412388
2015 Histone lysine methyltransferase Ezh1 promotes TLR-triggered inflammatory cytokine production by suppressing Tollip. Journal of immunology (Baltimore, Md. : 1950) 49 25687760
2022 Tollip Orchestrates Macrophage Polarization to Alleviate Intestinal Mucosal Inflammation. Journal of Crohn's & colitis 48 35134154
2022 TOLLIP-mediated autophagic degradation pathway links the VCP-TMEM63A-DERL1 signaling axis to triple-negative breast cancer progression. Autophagy 47 35920704
2017 Tollip Deficiency Alters Atherosclerosis and Steatosis by Disrupting Lipophagy. Journal of the American Heart Association 42 28396568
2017 Hyaluronic acid 35 normalizes TLR4 signaling in Kupffer cells from ethanol-fed rats via regulation of microRNA291b and its target Tollip. Scientific reports 42 29142263
2013 Toll-interacting protein (Tollip) negatively regulates pressure overload-induced ventricular hypertrophy in mice. Cardiovascular research 42 24285748
2010 Salmonid Tollip and MyD88 factors can functionally replace their mammalian orthologues in TLR-mediated trout SAA promoter activation. Developmental and comparative immunology 42 20813127
2021 Potential clinical utility of MUC5B und TOLLIP single nucleotide polymorphisms (SNPs) in the management of patients with IPF. Orphanet journal of rare diseases 41 33639995
2011 Escherichia coli producing CNF1 toxin hijacks Tollip to trigger Rac1-dependent cell invasion. Traffic (Copenhagen, Denmark) 41 21291504
2009 Expression and function of toll-like receptor 8 and Tollip in colonic epithelial cells from patients with inflammatory bowel disease. Scandinavian journal of gastroenterology 41 18985539
2013 Quercetin negatively regulates TLR4 signaling induced by lipopolysaccharide through Tollip expression. Biochemical and biophysical research communications 40 23353651
2023 The MGF300-2R protein of African swine fever virus is associated with viral pathogenicity by promoting the autophagic degradation of IKKα and IKKβ through the recruitment of TOLLIP. PLoS pathogens 38 37566637
2018 Epigallocatechin-3-Gallate Regulates Anti-Inflammatory Action Through 67-kDa Laminin Receptor-Mediated Tollip Signaling Induction in Lipopolysaccharide-Stimulated Human Intestinal Epithelial Cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 37 29723847
2013 Ubiquitin interacts with the Tollip C2 and CUE domains and inhibits binding of Tollip to phosphoinositides. The Journal of biological chemistry 36 23880770
2011 The C2 domain of Tollip, a Toll-like receptor signalling regulator, exhibits broad preference for phosphoinositides. The Biochemical journal 35 21294713
2007 The death domain of IRAK-1: an oligomerization domain mediating interactions with MyD88, Tollip, IRAK-1, and IRAK-4. Biochemical and biophysical research communications 33 17276401
2008 Tollip, a negative regulator of TLR-signalling, is encoded by twin genes in salmonid fish. Fish & shellfish immunology 32 18502148
2018 Leishmania donovani Exploits Tollip, a Multitasking Protein, To Impair TLR/IL-1R Signaling for Its Survival in the Host. Journal of immunology (Baltimore, Md. : 1950) 31 29907707
2016 Tollip SNP rs5743899 modulates human airway epithelial responses to rhinovirus infection. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 31 27513438
2012 PINK1 positively regulates IL-1β-mediated signaling through Tollip and IRAK1 modulation. Journal of neuroinflammation 31 23244239
2020 Autophagy Receptor Tollip Facilitates Bacterial Autophagy by Recruiting Galectin-7 in Response to Group A Streptococcus Infection. Frontiers in cellular and infection microbiology 30 33425778
2017 Green Tea Polyphenol EGCG Upregulates Tollip Expression by Suppressing Elf-1 Expression. Journal of immunology (Baltimore, Md. : 1950) 30 28954885
2012 Identification, characterization and the interaction of Tollip and IRAK-1 in grass carp (Ctenopharyngodon idellus). Fish & shellfish immunology 30 22659441
2014 Grouper (Epinephelus coioides) MyD88 and Tollip: intracellular localization and signal transduction function. Fish & shellfish immunology 29 25449381
2016 Tollip, an early regulator of the acute inflammatory response in the substantia nigra. Journal of neuroinflammation 28 27927222
2009 Tollip is a mediator of protein sumoylation. PloS one 28 19198660
2015 Polymorphisms in the TOLLIP Gene Influence Susceptibility to Cutaneous Leishmaniasis Caused by Leishmania guyanensis in the Amazonas State of Brazil. PLoS neglected tropical diseases 27 26107286
2019 Enhanced tumor immune surveillance through neutrophil reprogramming due to Tollip deficiency. JCI insight 25 30674719
2014 Activation of TOLLIP by porin prevents TLR2-associated IFN-γ and TNF-α-induced apoptosis of intestinal epithelial cells. Cellular signalling 25 25152369
2016 Deficiency in Toll-interacting protein (Tollip) skews inflamed yet incompetent innate leukocytes in vivo during DSS-induced septic colitis. Scientific reports 24 27703259
2015 Tollip is a critical mediator of cerebral ischaemia-reperfusion injury. The Journal of pathology 24 26011492
2011 Protective role of the ubiquitin binding protein Tollip against the toxicity of polyglutamine-expansion proteins. Neuroscience letters 24 21896309
2023 TOLLIP acts as a cargo adaptor to promote lysosomal degradation of aberrant ER membrane proteins. The EMBO journal 22 37929762
2018 Toll-Interacting Protein, Tollip, Inhibits IL-13-Mediated Pulmonary Eosinophilic Inflammation in Mice. Journal of innate immunity 22 29393212
2015 MiR-200 modulates coelomocytes antibacterial activities and LPS priming via targeting Tollip in Apostichopus japonicus. Fish & shellfish immunology 22 25910848
2014 Epigallocatechin-3-gallate-mediated Tollip induction through the 67-kDa laminin receptor negatively regulating TLR4 signaling in endothelial cells. Immunobiology 22 25109435
2022 PHLDA1 Suppresses TLR4-Triggered Proinflammatory Cytokine Production by Interaction With Tollip. Frontiers in immunology 21 35237256
2019 Chicken gga-miR-1306-5p targets Tollip and plays an important role in host response against Salmonella enteritidis infection. Journal of animal science and biotechnology 21 31338187
2015 Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP in Post-Lung Transplant Primary Graft Dysfunction Risk. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 21 26663441
2012 Expression and localization of TLR4 and its negative regulator Tollip in the placenta of early-onset and late-onset preeclampsia. Hypertension in pregnancy 21 22582869
2009 Diversification of TOLLIP isoforms in mouse and man. Mammalian genome : official journal of the International Mammalian Genome Society 21 19444506
2011 Transcription of the Tollip gene is elevated in intestinal epithelial cells through impaired O-GlcNAcylation-dependent nuclear translocation of the negative regulator Elf-1. Biochemical and biophysical research communications 20 21867680
2019 Tollip Inhibits ST2 Signaling in Airway Epithelial Cells Exposed to Type 2 Cytokines and Rhinovirus. Journal of innate immunity 19 30928973
2020 Polymorphisms of TLR2, TLR4 and TOLLIP and tuberculosis in two independent studies. Bioscience reports 18 32648572
2019 RM, a novel resveratrol derivative, attenuates inflammatory responses induced by lipopolysaccharide via selectively increasing the Tollip protein in macrophages: A partial mechanism with therapeutic potential in an inflammatory setting. International immunopharmacology 18 31835082
2018 Evaluation of TLR2, TLR4, and TOLLIP polymorphisms for their role in tuberculosis susceptibility. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 18 29924447
2015 Identification, characterization and expression profiling of the Tollip gene in Yesso scallop (Patinopecten yessoensis). Genes & genetic systems 18 26399769
2019 Peculiarities of the Expression of TLR4 and Inhibitor of TLR-Cascade Tollip in the Placenta in Earlyand Late-Onset Preeclampsia. Bulletin of experimental biology and medicine 17 30783843
2022 Protective effects of the notoginsenoside R1 on acute lung injury by regulating the miR-128-2-5p/Tollip signaling pathway in rats with severe acute pancreatitis. Innate immunity 15 35142579
2009 Tollip attenuated the hypertrophic response of cardiomyocytes induced by IL-1beta. Frontiers in bioscience (Landmark edition) 15 19273233
2009 Down syndrome candidate region-1 protein interacts with Tollip and positively modulates interleukin-1 receptor-mediated signaling. Biochimica et biophysica acta 15 19716405
2019 Molecular characterization, expression patterns, and functional analysis of toll-interacting protein (Tollip) in Japanese eel Anguilla japonica. Fish & shellfish immunology 14 31015066
2019 TOLLIP deficiency is associated with increased resistance to Legionella pneumophila pneumonia. Mucosal immunology 14 31462698
2024 Sideroflexin-1 promotes progression and sensitivity to lapatinib in triple-negative breast cancer by inhibiting TOLLIP-mediated autophagic degradation of CIP2A. Cancer letters 13 38849012
2019 Macrophage subsets exhibit distinct E. coli-LPS tolerisable cytokines associated with the negative regulators, IRAK-M and Tollip. PloS one 13 31120887
2013 Tollip-induced down-regulation of MARCH1. Results in immunology 13 24600555
2024 Pseudorabies virus UL38 attenuates the cGAS-STING signaling pathway by recruiting Tollip to promote STING for autophagy degradation. Virology journal 12 38720392
2022 Isorhapontigenin Modulates SOX9/TOLLIP Expression to Attenuate Cell Apoptosis and Oxidative Stress in Paraquat-Induced Acute Kidney Injury. Oxidative medicine and cellular longevity 12 35720190
2021 Overexpression of TOLLIP Protects against Acute Kidney Injury after Paraquat Intoxication through Inhibiting NLRP3 Inflammasome Activation Modulated by Toll-Like Receptor 2/4 Signaling. Mediators of inflammation 12 34335089
2022 Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway. Open medicine (Warsaw, Poland) 11 35434373
2015 Endocytic Adaptor Protein Tollip Inhibits Canonical Wnt Signaling. PloS one 11 26110841
2010 Backbone (1)H, (15)N, and (13)C resonance assignments and secondary structure of the Tollip CUE domain. Molecules and cells 11 20957454
2023 RNF167-mediated ubiquitination of Tollip inhibits TNF-α-triggered NF-κB and MAPK activation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 10 37410058
2022 Tollip Inhibits IL-33 Release and Inflammation in Influenza A Virus-Infected Mouse Airways. Journal of innate immunity 10 35760043
2021 Ctenopharyngodon idella Tollip regulates MyD88-induced NF-κB activation. Developmental and comparative immunology 10 34090930
2019 Monophosphoryl lipid A induces protection against LPS in medullary thick ascending limb through induction of Tollip and negative regulation of IRAK-1. American journal of physiology. Renal physiology 10 31241993
2015 Function analysis of fish Tollip gene in response to virus infection. Fish & shellfish immunology 10 26476109
2018 Tollip Negatively Regulates Vascular Smooth Muscle Cell-Mediated Neointima Formation by Suppressing Akt-Dependent Signaling. Journal of the American Heart Association 9 29887521
2025 Grass carp reovirus VP4 manipulates TOLLIP to degrade STING for inhibition of IFN production. Journal of virology 8 39807855
2025 IDR-driven TOLLIP condensates antagonize the innate antiviral immunity by promoting the deSUMOylation of MAVS. Cell reports 8 40022729
2024 TOLLIP inhibits lipid accumulation and the integrated stress response in alveolar macrophages to control Mycobacterium tuberculosis infection. Nature microbiology 8 38528148
2024 CAF-derived exosome-miR-3124-5p promotes malignant biological processes in NSCLC via the TOLLIP/TLR4-MyD88-NF-κB pathway. Oncology research 8 39735680
2023 Tollip deficiency exaggerates airway type 2 inflammation in mice exposed to allergen and influenza A virus: role of the ATP/IL-33 signaling axis. Frontiers in immunology 8 38124753
2021 CircRNA75 and CircRNA72 Function as the Sponge of MicroRNA-200 to Suppress Coelomocyte Apoptosis Via Targeting Tollip in Apostichopus japonicus. Frontiers in immunology 8 34868028
2014 Differential response to bacteria, and TOLLIP expression, in the human respiratory tract. BMJ open respiratory research 8 25478190
2022 Somatostatin attenuates intestinal epithelial barrier injury during acute intestinal ischemia-reperfusion through Tollip/Myeloiddifferentiationfactor 88/Nuclear factor kappa-B signaling. Bioengineered 7 35164650
2022 Tollip interaction with STAT3: a novel mechanism to regulate human airway epithelial responses to type 2 cytokines. Respiratory research 7 35172835
2014 Tollip or not Tollip: what are the evolving questions behind it? PloS one 7 24828816
2022 TOLLIP Optimizes Dendritic Cell Maturation to Lipopolysaccharide and Mycobacterium tuberculosis. Journal of immunology (Baltimore, Md. : 1950) 6 35803695

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