The double-strand RNA-dependent protein kinase PKR plays a significant role in a sustained ER stress-induced apoptosis

Sustained ER stress leads to apoptosis. However, the exact mechanism still remains to be elucidated. Here, we demonstrate that the double strand RNA-dependent protein kinase (PKR) is involved in the ER stress-mediated signaling pathway. ER stress rapidly activated PKR, inducing the phosphorylation of eIF2 alpha, followed by the activation of the ATF4/CHOP pathway. ER-stress-mediated eIF2 alpha/ATF4/CHOP signaling and associated cell death was markedly reduced by PKR knockdown. We also found that PKR activation was mediated by PACT, the expression of which was elevated by ER-stress. These results indicate that the ER-stress-mediated eIF2 alpha/ATF4/CHOP/cell death pathway is, to some degree, dependent on PACT-mediated PKR activation apart from the PERK pathway. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.