2. Academic Validation
  3. The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production

The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production

  • Immunity. 2014 Sep 18;41(3):375-388. doi: 10.1016/j.immuni.2014.08.011.
Toshihiko Kobayashi 1,  Shiho Shimabukuro-Demoto 2,  Reiko Yoshida-Sugitani 2,  Kaori Furuyama-Tanaka 2,  Hitomi Karyu 2,  Yuki Sugiura 3,  Yukiko Shimizu 4,  Toshiaki Hosaka 5,  Motohito Goto 4,  Norihiro Kato 6,  Tadashi Okamura 4,  Makoto Suematsu 7,  Shigeyuki Yokoyama 5,  Noriko Toyama-Sorimachi 8
Affiliations

Affiliations

  • 1 Department of Molecular Immunology and Inflammation, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan. Electronic address: [email protected].
  • 2 Department of Molecular Immunology and Inflammation, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
  • 3 Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; JST Precursory Research for Embryonic Science and Technology (PRESTO) Project, 4-1-8 Honcho Kawaguchi, Saitama, 332-0012, Japan.
  • 4 Department of Infectious Disease, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
  • 5 RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
  • 6 Department of Gene Diagnostics and Therapeutics, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
  • 7 Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Japan Science and Technology Agency, Exploratory Research for Advanced Technology (ERATO) Suematsu Gas Biology Project, Tokyo 160-8582, Japan.
  • 8 Department of Molecular Immunology and Inflammation, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan. Electronic address: [email protected].
PMID: 25238095 DOI: 10.1016/j.immuni.2014.08.011
Abstract

SLC15A4 is a lysosome-resident, proton-coupled amino-acid transporter that moves histidine and oligopeptides from inside the lysosome to the cytosol of eukaryotic cells. SLC15A4 is required for Toll-like Receptor 7 (TLR7)- and TLR9-mediated type I interferon (IFN-I) productions in plasmacytoid dendritic cells (pDCs) and is involved in the pathogenesis of certain diseases including lupus-like autoimmunity. How SLC15A4 contributes to diseases is largely unknown. Here we have shown that B cell SLC15A4 was crucial for TLR7-triggered IFN-I and autoantibody productions in a mouse lupus model. SLC15A4 loss disturbed the endolysosomal pH regulation and probably the v-ATPase integrity, and these changes were associated with disruption of the mTOR pathway, leading to failure of the IFN regulatory factor 7 (IRF7)-IFN-I regulatory circuit. Importantly, SLC15A4's transporter activity was necessary for the TLR-triggered cytokine production. Our findings revealed that SLC15A4-mediated optimization of the endolysosomal state is integral to a TLR7-triggered, mTOR-dependent IRF7-IFN-I circuit that leads to autoantibody production.

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