TOLLIP explained

Toll interacting protein, also known as TOLLIP, is an inhibitory adaptor protein that in humans is encoded by the TOLLIP gene.^{[1] [2] [3]}

Function and regulation

It is an inhibitory adaptor protein within Toll-like receptors (TLR).^[4] The TLR pathway is a part of the 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.^[5] 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.^[6]

Clinical significance

Polymorphisms in TLR genes have been implicated in various diseases like atopic dermatitis.^[7] Recently, variations in the TOLLIP gene have been associated with tuberculosis and idiopathic pulmonary fibrosis.^{[8] [9]}

Interactions

TOLLIP has been shown to interact with TOM1,^[10] TLR 2,^[11] TLR 4^[11] and IL1RAP.

Further reading

• Nilsen KH . Malignant lymphoma and rheumatic symptoms . The New Zealand Medical Journal . 83 . 563 . 320–322 . May 1976 . 1085432 .
• Volpe F, Clatworthy J, Kaptein A, Maschera B, Griffin AM, Ray K . 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 . December 1997 . 9426216 . 10.1016/S0014-5793(97)01426-9 . 1997FEBSL.419...41V . 39772937 .
• Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, Lewis A, Ray K, Tschopp J, Volpe F . 6 . Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor . Nature Cell Biology . 2 . 6 . 346–351 . June 2000 . 10854325 . 10.1038/35014038 . 32036101 .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–1795 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Bulut Y, Faure E, Thomas L, Equils O, Arditi M . 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 . Journal of Immunology . 167 . 2 . 987–994 . July 2001 . 11441107 . 10.4049/jimmunol.167.2.987 . free .
• Zhang G, Ghosh S . Negative regulation of toll-like receptor-mediated signaling by Tollip . The Journal of Biological Chemistry . 277 . 9 . 7059–7065 . March 2002 . 11751856 . 10.1074/jbc.M109537200 . free .
• Yamakami M, Yoshimori T, Yokosawa H . Tom1, a VHS domain-containing protein, interacts with tollip, ubiquitin, and clathrin . The Journal of Biological Chemistry . 278 . 52 . 52865–52872 . December 2003 . 14563850 . 10.1074/jbc.M306740200 . free .
• Katoh Y, Shiba Y, Mitsuhashi H, Yanagida Y, Takatsu H, Nakayama K . Tollip and Tom1 form a complex and recruit ubiquitin-conjugated proteins onto early endosomes . The Journal of Biological Chemistry . 279 . 23 . 24435–24443 . June 2004 . 15047686 . 10.1074/jbc.M400059200 . free .
• Lehner B, Sanderson CM . A protein interaction framework for human mRNA degradation . Genome Research . 14 . 7 . 1315–1323 . July 2004 . 15231747 . 442147 . 10.1101/gr.2122004 .
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A . 6 . From ORFeome to biology: a functional genomics pipeline . Genome Research . 14 . 10B . 2136–2144 . October 2004 . 15489336 . 528930 . 10.1101/gr.2576704 .
• Ohnuma K, Yamochi T, Uchiyama M, Nishibashi K, Iwata S, Hosono O, Kawasaki H, Tanaka H, Dang NH, Morimoto C . 6 . CD26 mediates dissociation of Tollip and IRAK-1 from caveolin-1 and induces upregulation of CD86 on antigen-presenting cells . Molecular and Cellular Biology . 25 . 17 . 7743–7757 . September 2005 . 16107720 . 1190283 . 10.1128/MCB.25.17.7743-7757.2005 .
• Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S . 6 . The LIFEdb database in 2006 . Nucleic Acids Research . 34 . Database issue . D415–D418 . January 2006 . 16381901 . 1347501 . 10.1093/nar/gkj139 .
• Katoh Y, Imakagura H, Futatsumori M, Nakayama K . Recruitment of clathrin onto endosomes by the Tom1-Tollip complex . Biochemical and Biophysical Research Communications . 341 . 1 . 143–149 . March 2006 . 16412388 . 10.1016/j.bbrc.2005.12.156 .
• Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY . 6 . A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration . Cell . 125 . 4 . 801–814 . May 2006 . 16713569 . 10.1016/j.cell.2006.03.032 . 13709685 . free .
• Brissoni B, Agostini L, Kropf M, Martinon F, Swoboda V, Lippens S, Everett H, Aebi N, Janssens S, Meylan E, Felberbaum-Corti M, Hirling H, Gruenberg J, Tschopp J, Burns K . 6 . Intracellular trafficking of interleukin-1 receptor I requires Tollip . Current Biology . 16 . 22 . 2265–2270 . November 2006 . 17113392 . 10.1016/j.cub.2006.09.062 . 13938932 . free . 2006CBio...16.2265B .

Notes and References

1. Web site: Entrez Gene: TOLLIP toll interacting protein.
2. Volpe F, Clatworthy J, Kaptein A, Maschera B, Griffin AM, Ray K . 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 . December 1997 . 9426216 . 10.1016/S0014-5793(97)01426-9 . 1997FEBSL.419...41V . 39772937 .
3. Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, Lewis A, Ray K, Tschopp J, Volpe F . 6 . Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor . Nature Cell Biology . 2 . 6 . 346–351 . June 2000 . 10854325 . 10.1038/35014038 . 32036101 .
4. Bulut Y, Faure E, Thomas L, Equils O, Arditi M . 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 . Journal of Immunology . 167 . 2 . 987–994 . July 2001 . 11441107 . 10.4049/jimmunol.167.2.987 . free .
5. Li T, Hu J, Li L . Characterization of Tollip protein upon Lipopolysaccharide challenge . Molecular Immunology . 41 . 1 . 85–92 . May 2004 . 15140579 . 10.1016/j.molimm.2004.03.009 .
6. Kowalski EJ, Li L . Toll-Interacting Protein in Resolving and Non-Resolving Inflammation . Frontiers in Immunology . 8 . 511 . 511 . May 2017 . 28529512 . 10.3389/fimmu.2017.00511 . 5418219 . free .
7. Schimming TT, Parwez Q, Petrasch-Parwez E, Nothnagel M, Epplen JT, Hoffjan S . Association of toll-interacting protein gene polymorphisms with atopic dermatitis . BMC Dermatology . 7 . 3 . March 2007 . 17362526 . 1832210 . 10.1186/1471-5945-7-3 . free .
8. Shah JA, Vary JC, Chau TT, Bang ND, Yen NT, Farrar JJ, Dunstan SJ, Hawn TR . 6 . Human TOLLIP regulates TLR2 and TLR4 signaling and its polymorphisms are associated with susceptibility to tuberculosis . Journal of Immunology . 189 . 4 . 1737–1746 . August 2012 . 22778396 . 3428135 . 10.4049/jimmunol.1103541 .
9. Noth I, Zhang Y, Ma SF, Flores C, Barber M, Huang Y, Broderick SM, Wade MS, Hysi P, Scuirba J, Richards TJ, Juan-Guardela BM, Vij R, Han MK, Martinez FJ, Kossen K, Seiwert SD, Christie JD, Nicolae D, Kaminski N, Garcia JG . 6 . Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study . The Lancet. Respiratory Medicine . 1 . 4 . 309–317 . June 2013 . 24429156 . 3894577 . 10.1016/S2213-2600(13)70045-6 .
10. Yamakami M, Yoshimori T, Yokosawa H . Tom1, a VHS domain-containing protein, interacts with tollip, ubiquitin, and clathrin . The Journal of Biological Chemistry . 278 . 52 . 52865–52872 . December 2003 . 14563850 . 10.1074/jbc.M306740200 . free .
11. Zhang G, Ghosh S . Negative regulation of toll-like receptor-mediated signaling by Tollip . The Journal of Biological Chemistry . 277 . 9 . 7059–7065 . March 2002 . 11751856 . 10.1074/jbc.M109537200 . free .