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Constitutive role of GADD 34 and CR eP in cancellation of phospho‐ eIF 2α‐dependent translational attenuation and insulin biosynthesis in pancreatic β cells
Author(s) -
Akai Ryoko,
Hosoda Akira,
Yoshino Mayuko,
Iwawaki Takao
Publication year - 2015
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12279
Subject(s) - endoplasmic reticulum , insulin , biology , unfolded protein response , phosphorylation , protein phosphatase 1 , microbiology and biotechnology , insulin receptor , kinase , eukaryotic initiation factor , protein biosynthesis , phosphatase , medicine , messenger rna , endocrinology , biochemistry , translation (biology) , insulin resistance , gene
Insulin biosynthesis has been well characterized with respect to transcriptional and post‐translational regulation. However, the relationship between translational regulation of insulin and protein quality control in the endoplasmic reticulum ( ER ) remains to be clarified. Here we carried out forced expression of insulin in non‐insulin‐producing cells and compared activation level of ER stress‐responsive molecules between insulin‐producing cells and non‐insulin‐producing cells under normal culture condition or ER stress condition. Forced expression of insulin in non‐insulin‐producing cells caused severe ER stress with striking translational attenuation through phosphorylation of eIF 2α by activation of protein kinase RNA‐like endoplasmic reticulum kinase ( PERK ), resulting in inhibition of insulin production at the protein level. We also found that GADD 34 and CR eP are highly expressed in the cells that endogenously produce insulin and that eIF 2α shows constitutively low phosphorylation level in these cells although PERK is constitutively activated under both normal culture conditions and physiological conditions in the same cells. Inhibition of eIF 2α phosphatase further decreased insulin level in pancreatic β cells. These findings suggest that eIF 2α phosphorylation level is kept low by GADD 34‐ and/or CR eP‐regulated phosphatases in pancreatic β cells and that cancellation of phospho‐ eIF 2α‐dependent translational inhibition by the molecular mechanism contributes to mass production of insulin in pancreatic β cells.