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 language | English |
|---|---|
| Pages (from-to) | 375-388 |
| Number of pages | 14 |
| Journal | Immunity |
| Volume | 41 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2014 Sep 18 |
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ASJC Scopus subject areas
- Immunology and Allergy
- Infectious Diseases
- Immunology
- Medicine(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production
AU - Kobayashi, Toshihiko
AU - Shimabukuro-Demoto, Shiho
AU - Yoshida-Sugitani, Reiko
AU - Furuyama-Tanaka, Kaori
AU - Karyu, Hitomi
AU - Sugiura, Yuki
AU - Shimizu, Yukiko
AU - Hosaka, Toshiaki
AU - Goto, Motohito
AU - Kato, Norihiro
AU - Okamura, Tadashi
AU - Suematsu, Makoto
AU - Yokoyama, Shigeyuki
AU - Toyama-Sorimachi, Noriko
PY - 2014/9/18
Y1 - 2014/9/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84907962139&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84907962139&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2014.08.011
DO - 10.1016/j.immuni.2014.08.011
M3 - Article
C2 - 25238095
AN - SCOPUS:84907962139
VL - 41
SP - 375
EP - 388
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 3
ER -