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

44 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

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Toll-Like Receptor 7
Histidine
Antibody Formation
Lysosomes
Autoantibodies
Amino Acid Transport Systems
Interferon Type I
Oligopeptides
Eukaryotic Cells
Autoimmunity
Cytosol
Dendritic Cells
Adenosine Triphosphatases
Protons
B-Lymphocytes
Cytokines

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology
  • Medicine(all)

Cite this

Kobayashi, T., Shimabukuro-Demoto, S., Yoshida-Sugitani, R., Furuyama-Tanaka, K., Karyu, H., Sugiura, Y., ... 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

The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. / Kobayashi, Toshihiko; Shimabukuro-Demoto, Shiho; Yoshida-Sugitani, Reiko; Furuyama-Tanaka, Kaori; Karyu, Hitomi; Sugiura, Yuki; Shimizu, Yukiko; Hosaka, Toshiaki; Goto, Motohito; Kato, Norihiro; Okamura, Tadashi; Suematsu, Makoto; Yokoyama, Shigeyuki; Toyama-Sorimachi, Noriko.

In: Immunity, Vol. 41, No. 3, 18.09.2014, p. 375-388.

Research output: Contribution to journalArticle

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, vol. 41, no. 3, pp. 375-388. https://doi.org/10.1016/j.immuni.2014.08.011
Kobayashi, Toshihiko ; Shimabukuro-Demoto, Shiho ; Yoshida-Sugitani, Reiko ; Furuyama-Tanaka, Kaori ; Karyu, Hitomi ; Sugiura, Yuki ; Shimizu, Yukiko ; Hosaka, Toshiaki ; Goto, Motohito ; Kato, Norihiro ; Okamura, Tadashi ; Suematsu, Makoto ; Yokoyama, Shigeyuki ; Toyama-Sorimachi, Noriko. / The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. In: Immunity. 2014 ; Vol. 41, No. 3. pp. 375-388.
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