| Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. | |
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MedLine Citation:
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PMID: 16306937 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Toll-like receptors (TLRs) are activated by pathogen-associated molecular patterns to induce innate immune responses and production of pro-inflammatory cytokines, interferons and anti-inflammatory cytokines. TLRs activate downstream effectors through adaptors that contain Toll/interleukin-1 receptor (TIR) domains, but the mechanisms accounting for diversification of TLR effector functions are unclear. To dissect biochemically TLR signalling, we established a system for isolating signalling complexes assembled by dimerized adaptors. Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6. Using myeloid cells from TRAF3- and TRAF6-deficient mice, we show that TRAF3 is essential for the induction of type I interferons (IFN) and the anti-inflammatory cytokine interleukin-10 (IL-10), but is dispensable for expression of pro-inflammatory cytokines. In fact, TRAF3-deficient cells overproduce pro-inflammatory cytokines owing to defective IL-10 production. Despite their structural similarity, the functions of TRAF3 and TRAF6 are largely distinct. TRAF3 is also recruited to the adaptor TRIF (Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta) and is required for marshalling the protein kinase TBK1 (also called NAK) into TIR signalling complexes, thereby explaining its unique role in activation of the IFN response. |
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Authors:
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Hans Häcker; Vanessa Redecke; Blagoy Blagoev; Irina Kratchmarova; Li-Chung Hsu; Gang G Wang; Mark P Kamps; Eyal Raz; Hermann Wagner; Georg Häcker; Matthias Mann; Michael Karin |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2005-11-23 |
Journal Detail:
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Title: Nature Volume: 439 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2006 Jan |
Date Detail:
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Created Date: 2006-01-12 Completed Date: 2006-02-01 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
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Languages: eng Pagination: 204-7 Citation Subset: IM |
Affiliation:
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Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. Hans.Haecker@stjude.org |
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| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Proteins, Signal Transducing
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chemistry,
genetics,
metabolism Adaptor Proteins, Vesicular Transport / metabolism Animals Antigens, Differentiation / chemistry, genetics, metabolism Cell Line Dimerization Gene Expression Regulation Immunity, Innate Interferons / biosynthesis Interleukin-10 / biosynthesis Mice Myeloid Cells / metabolism Myeloid Differentiation Factor 88 Protein-Serine-Threonine Kinases / metabolism Receptors, Immunologic / chemistry, genetics, metabolism Signal Transduction* Substrate Specificity TNF Receptor-Associated Factor 3 / metabolism* TNF Receptor-Associated Factor 6 / deficiency, genetics, metabolism* Toll-Like Receptors / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Adaptor Proteins, Signal Transducing; 0/Adaptor Proteins, Vesicular Transport; 0/Antigens, Differentiation; 0/Myd88 protein, mouse; 0/Myeloid Differentiation Factor 88; 0/Receptors, Immunologic; 0/TICAM-1 protein, mouse; 0/TNF Receptor-Associated Factor 3; 0/TNF Receptor-Associated Factor 6; 0/Toll-Like Receptors; 130068-27-8/Interleukin-10; 9008-11-1/Interferons; EC 2.7.1.-/Tbk1 protein, mouse; EC 2.7.11.1/Protein-Serine-Threonine Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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