KDEL receptor 1 regulates T-cell homeostasis via PP1 that is a key phosphatase for ISR

Daisuke Kamimura (), Kokichi Katsunuma, Yasunobu Arima, Toru Atsumi, Jing-jing Jiang, Hidenori Bando, Jie Meng, Lavannya Sabharwal, Andrea Stofkova, Naoki Nishikawa, Hironao Suzuki, Hideki Ogura, Naoko Ueda, Mineko Tsuruoka, Masaya Harada, Junya Kobayashi, Takanori Hasegawa, Hisahiro Yoshida, Haruhiko Koseki, Ikuo Miura, Shigeharu Wakana, Keigo Nishida, Hidemitsu Kitamura, Toshiyuki Fukada, Toshio Hirano and Masaaki Murakami ()
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Daisuke Kamimura: Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University
Kokichi Katsunuma: Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University
Yasunobu Arima: Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University
Toru Atsumi: Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University
Jing-jing Jiang: Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University
Hidenori Bando: Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University
Jie Meng: Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University
Lavannya Sabharwal: Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University
Andrea Stofkova: Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University
Naoki Nishikawa: Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University
Hironao Suzuki: Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University
Hideki Ogura: Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University
Naoko Ueda: Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University
Mineko Tsuruoka: Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University
Masaya Harada: Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University
Junya Kobayashi: Radiation Biology Center, Kyoto University
Takanori Hasegawa: Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology
Hisahiro Yoshida: Laboratory for Immunogenetics, RIKEN Research Center for Allergy and Immunology
Haruhiko Koseki: Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology
Ikuo Miura: Technology and Development Team for Mouse Phenotype Analysis, RIKEN Bioresource Center
Shigeharu Wakana: Technology and Development Team for Mouse Phenotype Analysis, RIKEN Bioresource Center
Keigo Nishida: Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology
Hidemitsu Kitamura: Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology
Toshiyuki Fukada: Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology
Toshio Hirano: Osaka University
Masaaki Murakami: Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract KDEL receptors are responsible for retrotransporting endoplasmic reticulum (ER) chaperones from the Golgi complex to the ER. Here we describe a role for KDEL receptor 1 (KDELR1) that involves the regulation of integrated stress responses (ISR) in T cells. Designing and using an N-ethyl-N-nitrosourea (ENU)-mutant mouse line, T-Red (naïve T-cell reduced), we show that a point mutation in KDELR1 is responsible for the reduction in the number of naïve T cells in this model owing to an increase in ISR. Mechanistic analysis shows that KDELR1 directly regulates protein phosphatase 1 (PP1), a key phosphatase for ISR in naïve T cells. T-Red KDELR1 does not associate with PP1, resulting in reduced phosphatase activity against eIF2α and subsequent expression of stress responsive genes including the proapoptotic factor Bim. These results demonstrate that KDELR1 regulates naïve T-cell homeostasis by controlling ISR.

Date: 2015
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DOI: 10.1038/ncomms8474

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