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

Research output: Contribution to journalArticle

55 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)375-388
Number of pages14
JournalImmunity
Volume41
Issue number3
DOIs
Publication statusPublished - 2014 Sep 18

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Kobayashi, T., Shimabukuro-Demoto, S., Yoshida-Sugitani, R., Furuyama-Tanaka, K., Karyu, H., Sugiura, Y., Shimizu, Y., Hosaka, T., Goto, M., Kato, N., Okamura, T., Suematsu, M., Yokoyama, S., & Toyama-Sorimachi, N. (2014). The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. Immunity, 41(3), 375-388. https://doi.org/10.1016/j.immuni.2014.08.011