# TOLLIP

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Protein-coding gene in the species Homo sapiens

TOLLIP Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1WGL, 2N31 Identifiers Aliases TOLLIP, IL-1RAcPIP, toll interacting protein External IDs OMIM: 606277; MGI: 1891808; HomoloGene: 10375; GeneCards: TOLLIP; OMA:TOLLIP - orthologs Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11p15.5 Start 1,274,371 bp[1] End 1,309,654 bp[1] Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7|7 F5 Start 141,428,550 bp[2] End 141,472,244 bp[2] RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right frontal lobe anterior cingulate cortex prefrontal cortex left testis right testis dorsolateral prefrontal cortex right lobe of liver Brodmann area 9 right hemisphere of cerebellum amygdala Top expressed in spermatocyte ankle joint dentate gyrus of hippocampal formation granule cell cumulus cell spermatid olfactory epithelium cerebellar cortex seminiferous tubule medial dorsal nucleus gastrula More reference expression data BioGPS More reference expression data Gene ontology Molecular function signal transducer activity Toll-like receptor binding SUMO binding kinase binding protein binding interleukin-1, type I receptor binding ubiquitin protein ligase binding ubiquitin conjugating enzyme binding ubiquitin binding Cellular component interleukin-18 receptor complex cytosol nuclear body perinuclear region of cytoplasm interleukin-1 receptor complex extracellular exosome extracellular region cytoplasm azurophil granule lumen specific granule lumen Biological process intracellular signal transduction epithelial cell differentiation phosphorylation immune system process leukocyte activation cell-cell signaling positive regulation of protein sumoylation autophagy protein localization to endosome innate immune response inflammatory response signal transduction ubiquitin-dependent protein catabolic process neutrophil degranulation interleukin-1-mediated signaling pathway Sources:Amigo / QuickGO Orthologs Species Human Mouse Entrez 54472 54473 Ensembl ENSG00000078902 ENSMUSG00000025139 UniProt Q9H0E2 Q6FIE9 Q9QZ06 RefSeq (mRNA) NM_019009 NM_001318512 NM_001318514 NM_001318515 NM_001318516 NM_023764 NM_001347562 RefSeq (protein) NP_001305441 NP_001305443 NP_001305444 NP_001305445 NP_061882 NP_061882.2 NP_001334491 NP_076253 Location (UCSC) Chr 11: 1.27 – 1.31 Mb Chr 7: 141.43 – 141.47 Mb PubMed search [3] [4] Wikidata View/Edit Human View/Edit Mouse

**Toll interacting protein**, also known as **TOLLIP**, is an inhibitory [adaptor protein](/source/Signal_transducing_adaptor_protein) that in humans is encoded by the *TOLLIP* [gene](/source/Gene).[5][6][7]

## Function and regulation

It is an inhibitory adaptor protein within [Toll-like receptors](/source/Toll-like_receptor) (TLR).[8] The TLR pathway is a part of the [innate immune system](/source/Innate_immune_system) that recognizes structurally conserved molecular patterns of microbial pathogens, leading to an inflammatory immune response.

Tollip interacts with cellular and subcellular membrane compartments such as endosome and lysosome through its C2 domain binding with phosphoinositides.[9] By coordinating organelle communications, Tollip can contribute to the fusion of endo-lysosome and autophagosome. Mice with Tollip deletion exhibit elevated risks for inflammatory diseases such as atherosclerosis and [neurodegeneration](/source/Neurodegeneration).[10]

## Clinical significance

[Polymorphisms](/source/Polymorphism_(biology)) in TLR genes have been implicated in various diseases like [atopic dermatitis](/source/Atopic_dermatitis).[11] Recently, variations in the TOLLIP gene have been associated with tuberculosis and idiopathic pulmonary fibrosis.[12][13]

## Interactions

TOLLIP has been shown to [interact](/source/Protein-protein_interaction) with [TOM1](/source/TOM1),[14] [TLR 2](/source/TLR_2),[15] [TLR 4](/source/TLR_4)[15] and [IL1RAP](/source/IL1RAP).[7]

## References

1. ^ [***a***](#cite_ref-refGRCh38Ensembl_1-0) [***b***](#cite_ref-refGRCh38Ensembl_1-1) [***c***](#cite_ref-refGRCh38Ensembl_1-2) [GRCh38: Ensembl release 89: ENSG00000078902](http://May2017.archive.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000078902) – [Ensembl](/source/Ensembl_genome_database_project), May 2017

1. ^ [***a***](#cite_ref-refGRCm38Ensembl_2-0) [***b***](#cite_ref-refGRCm38Ensembl_2-1) [***c***](#cite_ref-refGRCm38Ensembl_2-2) [GRCm38: Ensembl release 89: ENSMUSG00000025139](http://May2017.archive.ensembl.org/Mus_musculus/Gene/Summary?db=core;g=ENSMUSG00000025139) – [Ensembl](/source/Ensembl_genome_database_project), May 2017

1. **[^](#cite_ref-3)** ["Human PubMed Reference:"](https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Link&LinkName=gene_pubmed&from_uid=54472). *National Center for Biotechnology Information, U.S. National Library of Medicine*.

1. **[^](#cite_ref-4)** ["Mouse PubMed Reference:"](https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Link&LinkName=gene_pubmed&from_uid=54473). *National Center for Biotechnology Information, U.S. National Library of Medicine*.

1. **[^](#cite_ref-entrez_5-0)** ["Entrez Gene: TOLLIP toll interacting protein"](https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=54472).

1. **[^](#cite_ref-pmid9426216_6-0)** Volpe F, Clatworthy J, Kaptein A, Maschera B, Griffin AM, Ray K (December 1997). "The IL1 receptor accessory protein is responsible for the recruitment of the interleukin-1 receptor associated kinase to the IL1/IL1 receptor I complex". *FEBS Letters*. **419** (1): 41–44. [Bibcode](/source/Bibcode_(identifier)):[1997FEBSL.419...41V](https://ui.adsabs.harvard.edu/abs/1997FEBSL.419...41V). [doi](/source/Doi_(identifier)):[10.1016/S0014-5793(97)01426-9](https://doi.org/10.1016%2FS0014-5793%2897%2901426-9). [PMID](/source/PMID_(identifier)) [9426216](https://pubmed.ncbi.nlm.nih.gov/9426216). [S2CID](/source/S2CID_(identifier)) [39772937](https://api.semanticscholar.org/CorpusID:39772937).

1. ^ [***a***](#cite_ref-pmid10854325_7-0) [***b***](#cite_ref-pmid10854325_7-1) Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, et al. (June 2000). "Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor". *Nature Cell Biology*. **2** (6): 346–351. [doi](/source/Doi_(identifier)):[10.1038/35014038](https://doi.org/10.1038%2F35014038). [PMID](/source/PMID_(identifier)) [10854325](https://pubmed.ncbi.nlm.nih.gov/10854325). [S2CID](/source/S2CID_(identifier)) [32036101](https://api.semanticscholar.org/CorpusID:32036101).

1. **[^](#cite_ref-pmid11441107_8-0)** Bulut Y, Faure E, Thomas L, Equils O, Arditi M (July 2001). ["Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein A lipoprotein: role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor 2 signaling"](https://doi.org/10.4049%2Fjimmunol.167.2.987). *Journal of Immunology*. **167** (2): 987–994. [doi](/source/Doi_(identifier)):[10.4049/jimmunol.167.2.987](https://doi.org/10.4049%2Fjimmunol.167.2.987). [PMID](/source/PMID_(identifier)) [11441107](https://pubmed.ncbi.nlm.nih.gov/11441107).

1. **[^](#cite_ref-pmid15140579_9-0)** Li T, Hu J, Li L (May 2004). "Characterization of Tollip protein upon Lipopolysaccharide challenge". *Molecular Immunology*. **41** (1): 85–92. [doi](/source/Doi_(identifier)):[10.1016/j.molimm.2004.03.009](https://doi.org/10.1016%2Fj.molimm.2004.03.009). [PMID](/source/PMID_(identifier)) [15140579](https://pubmed.ncbi.nlm.nih.gov/15140579).

1. **[^](#cite_ref-pmid28529512_10-0)** Kowalski EJ, Li L (May 2017). ["Toll-Interacting Protein in Resolving and Non-Resolving Inflammation"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418219). *Frontiers in Immunology*. **8** (511): 511. [doi](/source/Doi_(identifier)):[10.3389/fimmu.2017.00511](https://doi.org/10.3389%2Ffimmu.2017.00511). [PMC](/source/PMC_(identifier)) [5418219](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418219). [PMID](/source/PMID_(identifier)) [28529512](https://pubmed.ncbi.nlm.nih.gov/28529512).

1. **[^](#cite_ref-pmid17362526_11-0)** Schimming TT, Parwez Q, Petrasch-Parwez E, Nothnagel M, Epplen JT, Hoffjan S (March 2007). ["Association of toll-interacting protein gene polymorphisms with atopic dermatitis"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1832210). *BMC Dermatology*. **7**: 3. [doi](/source/Doi_(identifier)):[10.1186/1471-5945-7-3](https://doi.org/10.1186%2F1471-5945-7-3). [PMC](/source/PMC_(identifier)) [1832210](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1832210). [PMID](/source/PMID_(identifier)) [17362526](https://pubmed.ncbi.nlm.nih.gov/17362526).

1. **[^](#cite_ref-12)** Shah JA, Vary JC, Chau TT, Bang ND, Yen NT, Farrar JJ, et al. (August 2012). ["Human TOLLIP regulates TLR2 and TLR4 signaling and its polymorphisms are associated with susceptibility to tuberculosis"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428135). *Journal of Immunology*. **189** (4): 1737–1746. [doi](/source/Doi_(identifier)):[10.4049/jimmunol.1103541](https://doi.org/10.4049%2Fjimmunol.1103541). [PMC](/source/PMC_(identifier)) [3428135](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428135). [PMID](/source/PMID_(identifier)) [22778396](https://pubmed.ncbi.nlm.nih.gov/22778396).

1. **[^](#cite_ref-13)** Noth I, Zhang Y, Ma SF, Flores C, Barber M, Huang Y, et al. (June 2013). ["Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894577). *The Lancet. Respiratory Medicine*. **1** (4): 309–317. [doi](/source/Doi_(identifier)):[10.1016/S2213-2600(13)70045-6](https://doi.org/10.1016%2FS2213-2600%2813%2970045-6). [PMC](/source/PMC_(identifier)) [3894577](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894577). [PMID](/source/PMID_(identifier)) [24429156](https://pubmed.ncbi.nlm.nih.gov/24429156).

1. **[^](#cite_ref-pmid14563850_14-0)** Yamakami M, Yoshimori T, Yokosawa H (December 2003). ["Tom1, a VHS domain-containing protein, interacts with tollip, ubiquitin, and clathrin"](https://doi.org/10.1074%2Fjbc.M306740200). *The Journal of Biological Chemistry*. **278** (52): 52865–52872. [doi](/source/Doi_(identifier)):[10.1074/jbc.M306740200](https://doi.org/10.1074%2Fjbc.M306740200). [PMID](/source/PMID_(identifier)) [14563850](https://pubmed.ncbi.nlm.nih.gov/14563850).

1. ^ [***a***](#cite_ref-pmid11751856_15-0) [***b***](#cite_ref-pmid11751856_15-1) Zhang G, Ghosh S (March 2002). ["Negative regulation of toll-like receptor-mediated signaling by Tollip"](https://doi.org/10.1074%2Fjbc.M109537200). *The Journal of Biological Chemistry*. **277** (9): 7059–7065. [doi](/source/Doi_(identifier)):[10.1074/jbc.M109537200](https://doi.org/10.1074%2Fjbc.M109537200). [PMID](/source/PMID_(identifier)) [11751856](https://pubmed.ncbi.nlm.nih.gov/11751856).

## Further reading

- Nilsen KH (May 1976). "Malignant lymphoma and rheumatic symptoms". *The New Zealand Medical Journal*. **83** (563): 320–322. [PMID](/source/PMID_(identifier)) [1085432](https://pubmed.ncbi.nlm.nih.gov/1085432).

- Volpe F, Clatworthy J, Kaptein A, Maschera B, Griffin AM, Ray K (December 1997). "The IL1 receptor accessory protein is responsible for the recruitment of the interleukin-1 receptor associated kinase to the IL1/IL1 receptor I complex". *FEBS Letters*. **419** (1): 41–44. [Bibcode](/source/Bibcode_(identifier)):[1997FEBSL.419...41V](https://ui.adsabs.harvard.edu/abs/1997FEBSL.419...41V). [doi](/source/Doi_(identifier)):[10.1016/S0014-5793(97)01426-9](https://doi.org/10.1016%2FS0014-5793%2897%2901426-9). [PMID](/source/PMID_(identifier)) [9426216](https://pubmed.ncbi.nlm.nih.gov/9426216). [S2CID](/source/S2CID_(identifier)) [39772937](https://api.semanticscholar.org/CorpusID:39772937).

- Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, et al. (June 2000). "Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor". *Nature Cell Biology*. **2** (6): 346–351. [doi](/source/Doi_(identifier)):[10.1038/35014038](https://doi.org/10.1038%2F35014038). [PMID](/source/PMID_(identifier)) [10854325](https://pubmed.ncbi.nlm.nih.gov/10854325). [S2CID](/source/S2CID_(identifier)) [32036101](https://api.semanticscholar.org/CorpusID:32036101).

- Hartley JL, Temple GF, Brasch MA (November 2000). ["DNA cloning using in vitro site-specific recombination"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC310948). *Genome Research*. **10** (11): 1788–1795. [doi](/source/Doi_(identifier)):[10.1101/gr.143000](https://doi.org/10.1101%2Fgr.143000). [PMC](/source/PMC_(identifier)) [310948](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC310948). [PMID](/source/PMID_(identifier)) [11076863](https://pubmed.ncbi.nlm.nih.gov/11076863).

- Bulut Y, Faure E, Thomas L, Equils O, Arditi M (July 2001). ["Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein A lipoprotein: role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor 2 signaling"](https://doi.org/10.4049%2Fjimmunol.167.2.987). *Journal of Immunology*. **167** (2): 987–994. [doi](/source/Doi_(identifier)):[10.4049/jimmunol.167.2.987](https://doi.org/10.4049%2Fjimmunol.167.2.987). [PMID](/source/PMID_(identifier)) [11441107](https://pubmed.ncbi.nlm.nih.gov/11441107).

- Zhang G, Ghosh S (March 2002). ["Negative regulation of toll-like receptor-mediated signaling by Tollip"](https://doi.org/10.1074%2Fjbc.M109537200). *The Journal of Biological Chemistry*. **277** (9): 7059–7065. [doi](/source/Doi_(identifier)):[10.1074/jbc.M109537200](https://doi.org/10.1074%2Fjbc.M109537200). [PMID](/source/PMID_(identifier)) [11751856](https://pubmed.ncbi.nlm.nih.gov/11751856).

- Yamakami M, Yoshimori T, Yokosawa H (December 2003). ["Tom1, a VHS domain-containing protein, interacts with tollip, ubiquitin, and clathrin"](https://doi.org/10.1074%2Fjbc.M306740200). *The Journal of Biological Chemistry*. **278** (52): 52865–52872. [doi](/source/Doi_(identifier)):[10.1074/jbc.M306740200](https://doi.org/10.1074%2Fjbc.M306740200). [PMID](/source/PMID_(identifier)) [14563850](https://pubmed.ncbi.nlm.nih.gov/14563850).

- Katoh Y, Shiba Y, Mitsuhashi H, Yanagida Y, Takatsu H, Nakayama K (June 2004). ["Tollip and Tom1 form a complex and recruit ubiquitin-conjugated proteins onto early endosomes"](https://doi.org/10.1074%2Fjbc.M400059200). *The Journal of Biological Chemistry*. **279** (23): 24435–24443. [doi](/source/Doi_(identifier)):[10.1074/jbc.M400059200](https://doi.org/10.1074%2Fjbc.M400059200). [PMID](/source/PMID_(identifier)) [15047686](https://pubmed.ncbi.nlm.nih.gov/15047686).

- Lehner B, Sanderson CM (July 2004). ["A protein interaction framework for human mRNA degradation"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC442147). *Genome Research*. **14** (7): 1315–1323. [doi](/source/Doi_(identifier)):[10.1101/gr.2122004](https://doi.org/10.1101%2Fgr.2122004). [PMC](/source/PMC_(identifier)) [442147](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC442147). [PMID](/source/PMID_(identifier)) [15231747](https://pubmed.ncbi.nlm.nih.gov/15231747).

- Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, et al. (October 2004). ["From ORFeome to biology: a functional genomics pipeline"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC528930). *Genome Research*. **14** (10B): 2136–2144. [doi](/source/Doi_(identifier)):[10.1101/gr.2576704](https://doi.org/10.1101%2Fgr.2576704). [PMC](/source/PMC_(identifier)) [528930](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC528930). [PMID](/source/PMID_(identifier)) [15489336](https://pubmed.ncbi.nlm.nih.gov/15489336).

- Ohnuma K, Yamochi T, Uchiyama M, Nishibashi K, Iwata S, Hosono O, et al. (September 2005). ["CD26 mediates dissociation of Tollip and IRAK-1 from caveolin-1 and induces upregulation of CD86 on antigen-presenting cells"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1190283). *Molecular and Cellular Biology*. **25** (17): 7743–7757. [doi](/source/Doi_(identifier)):[10.1128/MCB.25.17.7743-7757.2005](https://doi.org/10.1128%2FMCB.25.17.7743-7757.2005). [PMC](/source/PMC_(identifier)) [1190283](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1190283). [PMID](/source/PMID_(identifier)) [16107720](https://pubmed.ncbi.nlm.nih.gov/16107720).

- Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, et al. (January 2006). ["The LIFEdb database in 2006"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1347501). *Nucleic Acids Research*. **34** (Database issue): D415–D418. [doi](/source/Doi_(identifier)):[10.1093/nar/gkj139](https://doi.org/10.1093%2Fnar%2Fgkj139). [PMC](/source/PMC_(identifier)) [1347501](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1347501). [PMID](/source/PMID_(identifier)) [16381901](https://pubmed.ncbi.nlm.nih.gov/16381901).

- Katoh Y, Imakagura H, Futatsumori M, Nakayama K (March 2006). "Recruitment of clathrin onto endosomes by the Tom1-Tollip complex". *Biochemical and Biophysical Research Communications*. **341** (1): 143–149. [doi](/source/Doi_(identifier)):[10.1016/j.bbrc.2005.12.156](https://doi.org/10.1016%2Fj.bbrc.2005.12.156). [PMID](/source/PMID_(identifier)) [16412388](https://pubmed.ncbi.nlm.nih.gov/16412388).

- Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, et al. (May 2006). ["A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration"](https://doi.org/10.1016%2Fj.cell.2006.03.032). *Cell*. **125** (4): 801–814. [doi](/source/Doi_(identifier)):[10.1016/j.cell.2006.03.032](https://doi.org/10.1016%2Fj.cell.2006.03.032). [PMID](/source/PMID_(identifier)) [16713569](https://pubmed.ncbi.nlm.nih.gov/16713569). [S2CID](/source/S2CID_(identifier)) [13709685](https://api.semanticscholar.org/CorpusID:13709685).

- Brissoni B, Agostini L, Kropf M, Martinon F, Swoboda V, Lippens S, et al. (November 2006). ["Intracellular trafficking of interleukin-1 receptor I requires Tollip"](https://doi.org/10.1016%2Fj.cub.2006.09.062). *Current Biology*. **16** (22): 2265–2270. [Bibcode](/source/Bibcode_(identifier)):[2006CBio...16.2265B](https://ui.adsabs.harvard.edu/abs/2006CBio...16.2265B). [doi](/source/Doi_(identifier)):[10.1016/j.cub.2006.09.062](https://doi.org/10.1016%2Fj.cub.2006.09.062). [PMID](/source/PMID_(identifier)) [17113392](https://pubmed.ncbi.nlm.nih.gov/17113392). [S2CID](/source/S2CID_(identifier)) [13938932](https://api.semanticscholar.org/CorpusID:13938932).

v t e PDB gallery 1wgl: Solution Structure of CUE domain in the C-terminal of Human Toll-interacting Protein (Tollip)

v t e Signaling pathway: TLR signaling pathway TLRs TLR1 TLR2 TLR3 TLR4 TLR5 TLR6 TLR7 TLR8 TLR9 TLR10 TLR11 TLR12 TLR13 Other receptors CD14 LBP MD2 Downstream signalling IRAK1 IRAK2 IRAK3 IRAK4 IRF3 MAP3K7 MYD88 TAB1 TICAM1 TIRAP TOLLIP TRAF6

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Adapted from the Wikipedia article [TOLLIP](https://en.wikipedia.org/wiki/TOLLIP) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/TOLLIP?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.