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Immunity. 2014 Sep 18;41(3):375-388. doi: 10.1016/j.immuni.2014.08.011.

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

Author information

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: tkobayashi@ri.ncgm.go.jp.
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: nsorima@ri.ncgm.go.jp.

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.

PMID:
25238095
DOI:
10.1016/j.immuni.2014.08.011
[Indexed for MEDLINE]
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