| Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells. | |
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MedLine Citation:
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PMID: 21045126 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Despite their low frequency, plasmacytoid dendritic cells (pDCs) produce most of the type I IFN that is detectable in the blood following viral infection. The endosomal Toll-like receptors (TLRs) TLR7 and TLR9 are required for pDCs, as well as other cell types, to sense viral nucleic acids, but the mechanism by which signaling through these shared receptors results in the prodigious production of type I IFN by pDCs is not understood. We designed a genetic screen to identify proteins required for the development and specialized function of pDCs. One phenovariant, which we named feeble, showed abrogation of both TLR-induced type I IFN and proinflammatory cytokine production by pDCs, while leaving TLR responses intact in other cells. The feeble phenotype was mapped to a mutation in Slc15a4, which encodes the peptide/histidine transporter 1 (PHT1) and has not previously been implicated in pDC function. The identification of the feeble mutation led to our subsequent observations that AP-3, as well as the BLOC-1 and BLOC-2 Hermansky-Pudlak syndrome proteins are essential for pDC signaling through TLR7 and TLR9. These proteins are not necessary for TLR7 or TLR9 signaling in conventional DCs and thus comprise a membrane trafficking pathway uniquely required for endosomal TLR signaling in pDCs. |
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Authors:
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Amanda L Blasius; Carrie N Arnold; Philippe Georgel; Sophie Rutschmann; Yu Xia; Pei Lin; Charles Ross; Xiaohong Li; Nora G Smart; Bruce Beutler |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-11-02 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 107 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-18 Completed Date: 2010-12-21 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 19973-8 Citation Subset: IM |
Affiliation:
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Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Protein Complex 3
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metabolism* Animals Carrier Proteins / metabolism* Cell Membrane / metabolism Chromosome Mapping Dendritic Cells / cytology, immunology* Genetic Testing Hermanski-Pudlak Syndrome / metabolism* Interferon Type I / biosynthesis Lectins / metabolism* Membrane Transport Proteins / metabolism* Mice Mutation / genetics Nerve Tissue Proteins / metabolism* Protein Transport Signal Transduction / immunology Toll-Like Receptors / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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AI070167/AI/NIAID NIH HHS; HHSN272200700038C//PHS HHS |
| Chemical | |
Reg. No./Substance:
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0/Adaptor Protein Complex 3; 0/Bloc-2 protein, mouse; 0/Carrier Proteins; 0/Interferon Type I; 0/Lectins; 0/Membrane Transport Proteins; 0/Nerve Tissue Proteins; 0/Pldn protein, mouse; 0/Slc15a4 protein, mouse; 0/Toll-Like Receptors |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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