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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells
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Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells

机译：Slc15a4，AP-3和Hermansky-Pudlak综合征蛋白是浆细胞样树突状细胞Toll样受体信号转导所必需的

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摘要

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 feeib/e, showed abrogation of both TLR-induced type I IFN and pro-inflammatory 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.
机译：尽管浆细胞样树突状细胞（pDC）的频率较低，但在病毒感染后仍会在血液中产生大部分I型IFN。 pDC和其他细胞类型需要内体Toll样受体（TLR）TLR7和TLR9来感知病毒核酸，但是通过这些共享受体发出信号的机制导致IDC大量产生I干扰素不了解pDC。我们设计了一个基因筛选程序，以鉴定pDC的发育和特殊功能所需的蛋白质。一个表观变种，我们命名为Feeib / e，显示pDC消除了TLR诱导的I型IFN和促炎性细胞因子的产生，而在其他细胞中则保持了TLR反应的完整。微弱的表型被映射到Slc15a4中的一个突变，该突变编码肽/组氨酸转运蛋白1（PHT1），以前未涉及pDC功能。微弱突变的鉴定导致我们随后观察到，AP-3以及BLOC-1和BLOC-2 Hermansky-Pudlak综合征蛋白对于通过TLR7和TLR9传递pDC信号至关重要。这些蛋白质对于常规DC中的TLR7或TLR9信号不是必需的，因此包含pDC中内体TLR信号所特有的膜运输途径。

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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;

  • 作者单位

    Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037;

    Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037;

    Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037,Laboratoire d'lmmunogenetique Moleculaire Humaine, Centre de Re- cherche d'lmmunologie et d'Hematologie, Faculte de Medecine, 4 rue Kirschleger, Stras- bourg, Cedex 67085, France;

    Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037,Imperial College London, Faculty of Medicine, Du Cane Road, London W12 ONN, United Kingdom;

    Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037;

    Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037;

    Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037;

    Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037;

    Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037;

    Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    adapter protein 3; lysosome-related organelle; solute carrier; type Ⅰ interferon; vesicular trafficking;

    机译：衔接蛋白3;溶酶体相关细胞器溶质载体Ⅰ型干扰素;水泡运输;

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