The function of GADD34 is a recovery from a shutoff of protein synthesis induced by ER stress - elucidation by GADD34-deficient mice

GADD34 is a protein that is induced by stresses such as DNA damage. The function of mammalian GADD34 has been proposed by in vitro transfection, but its function in vivo has not yet been elucidated. Here we generated and analyzed GADD34 knockout mice. Despite their embryonic stage- and tissue-specific expressions, GADD34 knockout mice showed no abnormalities at fetal development and in early adult life. However, in GADD34(-/-) mouse embryonic fibroblasts (MEFs), recovery from a shutoff of protein synthesis was delayed when MEFs were exposed to endoplasmic reticulum (ER) stress. The phosphorylation of eukaryotic translation initiator factor 2alpha (eIF2alpha) at Ser51 induced by thapsigargin or DTT was prolonged in GADD34(-/-) MEF, although following treatment with tunicamycin, the eIF2alpha phosphorylation level did not change in either GADD34(+/+) or GADD34(-/-) cells. ER stress stimuli induced expressions of Bip (binding Ig protein) and CHOP (C/EBP homologous protein) in MEF of wild-type mice. These expressions were strongly reduced in GADD34(-/-) MEF, which suggests that GADD34 up-regulates Bip and CHOP. These results indicate that GADD34 works as a sensor of ER stress stimuli and recovers cells from shutoff of protein synthesis.