ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death

Jaeseok Han, Sung Hoon Back, Junguk Hur, Yu Hsuan Lin, Robert Gildersleeve, Jixiu Shan, Celvie L. Yuan, Dawid Krokowski, Shiyu Wang, Maria Hatzoglou, Michael S. Kilberg, Maureen A. Sartor, Randal J. Kaufman

Research output: Contribution to journalArticle

725 Scopus citations

Abstract

Protein misfolding in the endoplasmic reticulum (ER) leads to cell death through PERK-mediated phosphorylation of eIF2α, although the mechanism is not understood. ChIP-seq and mRNA-seq of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), key transcription factors downstream of p-eIF2α, demonstrated that they interact to directly induce genes encoding protein synthesis and the unfolded protein response, but not apoptosis. Forced expression of ATF4 and CHOP increased protein synthesis and caused ATP depletion, oxidative stress and cell death. The increased protein synthesis and oxidative stress were necessary signals for cell death. We show that eIF2α-phosphorylation-attenuated protein synthesis, and not Atf4 mRNA translation, promotes cell survival. These results show that transcriptional induction through ATF4 and CHOP increases protein synthesis leading to oxidative stress and cell death. The findings suggest that limiting protein synthesis will be therapeutic for diseases caused by protein misfolding in the ER.

Original languageEnglish (US)
Pages (from-to)481-490
Number of pages10
JournalNature Cell Biology
Volume15
Issue number5
DOIs
StatePublished - May 2013

ASJC Scopus subject areas

  • Cell Biology

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    Han, J., Back, S. H., Hur, J., Lin, Y. H., Gildersleeve, R., Shan, J., Yuan, C. L., Krokowski, D., Wang, S., Hatzoglou, M., Kilberg, M. S., Sartor, M. A., & Kaufman, R. J. (2013). ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nature Cell Biology, 15(5), 481-490. https://doi.org/10.1038/ncb2738