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

Toshihiko Kobayashi; Shiho Shimabukuro-Demoto; Reiko Yoshida-Sugitani; Kaori Furuyama-Tanaka; Hitomi Karyu; Yuki Sugiura; Yukiko Shimizu; Toshiaki Hosaka; Motohito Goto; Norihiro Kato; Tadashi Okamura; Makoto Suematsu; Shigeyuki Yokoyama; Noriko Toyama-Sorimachi

doi:10.1016/j.immuni.2014.08.011

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.

Authors

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies / immunology
Antibody Formation / immunology*
Autoantibodies / biosynthesis
B-Lymphocytes / immunology
Cells, Cultured
Immunoglobulin G / biosynthesis
Inflammation / immunology*
Interferon Regulatory Factor-7 / genetics
Interferon Regulatory Factor-7 / immunology
Interferon Type I / biosynthesis
Lupus Erythematosus, Systemic / immunology*
Lupus Erythematosus, Systemic / pathology
Lysosomes / physiology
Membrane Glycoproteins / immunology
Membrane Transport Proteins / genetics
Membrane Transport Proteins / immunology*
Mice
Mice, Knockout
Receptor, Interferon alpha-beta / genetics
TOR Serine-Threonine Kinases / immunology*
Toll-Like Receptor 7 / immunology
Toll-Like Receptor 9 / immunology
Vacuolar Proton-Translocating ATPases / genetics
Vacuolar Proton-Translocating ATPases / immunology

Substances

Antibodies
Autoantibodies
Ifnar1 protein, mouse
Immunoglobulin G
Interferon Regulatory Factor-7
Interferon Type I
Irf7 protein, mouse
Membrane Glycoproteins
Membrane Transport Proteins
Slc15a4 protein, mouse
Tlr7 protein, mouse
Tlr9 protein, mouse
Toll-Like Receptor 7
Toll-Like Receptor 9
Receptor, Interferon alpha-beta
mTOR protein, mouse
TOR Serine-Threonine Kinases
Vacuolar Proton-Translocating ATPases