title: KDEL receptor 1 regulates T-cell homeostasis via PP1 that is a key phosphatase for ISR.
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.
authors.affiliation: 1] Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan [2] Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita 565-0871, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kamimura
authors.affiliation: Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita 565-0871, Japan.
authors.forename: Kokichi
authors.initials: K
authors.lastname: Katsunuma
authors.affiliation: 1] Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan [2] Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita 565-0871, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Arima
authors.affiliation: 1] Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan [2] Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita 565-0871, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Atsumi
authors.affiliation: 1] Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan [2] Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita 565-0871, Japan.
authors.forename: Jing-jing
authors.initials: JJ
authors.lastname: Jiang
authors.affiliation: 1] Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan [2] Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita 565-0871, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Bando
authors.affiliation: 1] Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan [2] Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita 565-0871, Japan.
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
authors.affiliation: 1] Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan [2] Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita 565-0871, Japan.
authors.forename: Lavannya
authors.initials: L
authors.lastname: Sabharwal
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan.
authors.forename: Andrea
authors.initials: A
authors.lastname: Stofkova
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nishikawa
authors.affiliation: 1] Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan [2] Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita 565-0871, Japan.
authors.forename: Hironao
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: 1] Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan [2] Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita 565-0871, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ogura
authors.affiliation: Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita 565-0871, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Ueda
authors.affiliation: Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita 565-0871, Japan.
authors.forename: Mineko
authors.initials: M
authors.lastname: Tsuruoka
authors.affiliation: Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita 565-0871, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Harada
authors.affiliation: Radiation Biology Center, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kobayashi
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Laboratory for Immunogenetics, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Hisahiro
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Technology and Development Team for Mouse Phenotype Analysis, RIKEN Bioresource Center, 3-1-1 Koyadai, Tsukuba 305-0074, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Miura
authors.affiliation: Technology and Development Team for Mouse Phenotype Analysis, RIKEN Bioresource Center, 3-1-1 Koyadai, Tsukuba 305-0074, Japan.
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Wakana
authors.affiliation: Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Nishida
authors.affiliation: Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Kitamura
authors.affiliation: Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Fukada
authors.affiliation: Osaka University, 2-1, Yamada-oka, Suita 565-0871, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Hirano
authors.affiliation: 1] Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan [2] Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita 565-0871, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Murakami
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D007156:Immunologic Memory; D008565:Membrane Proteins / Q000378:metabolism; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010641:Phenotype; D017354:Point Mutation; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D015852:Eukaryotic Initiation Factor-2; C000606768:KDELR1 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D018000:Receptors, Peptide; D054645:Protein Phosphatase 1