title: The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production.
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.
authors.affiliation: 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: tkobayashi@ri.ncgm.go.jp.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: 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.
authors.forename: Shiho
authors.initials: S
authors.lastname: Shimabukuro-Demoto
authors.affiliation: 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.
authors.forename: Reiko
authors.initials: R
authors.lastname: Yoshida-Sugitani
authors.affiliation: 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.
authors.forename: Kaori
authors.initials: K
authors.lastname: Furuyama-Tanaka
authors.affiliation: 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.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Karyu
authors.affiliation: 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.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sugiura
authors.affiliation: Department of Infectious Disease, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hosaka
authors.affiliation: Department of Infectious Disease, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
authors.forename: Motohito
authors.initials: M
authors.lastname: Goto
authors.affiliation: Department of Gene Diagnostics and Therapeutics, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kato
authors.affiliation: Department of Infectious Disease, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okamura
authors.affiliation: 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.
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.affiliation: RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.affiliation: 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: nsorima@ri.ncgm.go.jp.
authors.forename: Noriko
authors.initials: N
authors.lastname: Toyama-Sorimachi
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D007074:Immunoglobulin G / Q000096:biosynthesis; D007249:Inflammation / Q000276:immunology*; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology; D007370:Interferon Type I / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008247:Lysosomes / Q000502:physiology; D008562:Membrane Glycoproteins / Q000276:immunology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000276:immunology
chemical_list: D000906:Antibodies; D001323:Autoantibodies; C508032:Ifnar1 protein, mouse; D007074:Immunoglobulin G; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; C494235:Irf7 protein, mouse; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C554281:Slc15a4 protein, mouse; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D053633:Receptor, Interferon alpha-beta; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D025262:Vacuolar Proton-Translocating ATPases