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.

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
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Vacuolar Proton-Translocating ATPases