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RESEARCH PAPER
1 Skirball Institute of Biomolecular Medicine and the Departments of Cell Biology, Medicine and Pharmacology, New York University School of Medicine, New York, New York 10016, USA; 2 Institute for Frontier Medical Sciences Kyoto University, Kyoto 606-8397, Japan
Unfolded and malfolded client proteins impose a stress on the endoplasmic reticulum (ER), which contributes to cell death in pathophysiological conditions. The transcription factor C/EBP homologous protein (CHOP) is activated by ER stress, and CHOP deletion protects against its lethal consequences. We find that CHOP directly activates GADD34, which promotes ER client protein biosynthesis by dephosphorylating phospho-Ser 51 of the 
-subunit of translation initiation factor 2 (eIF2) in stressed cells. Thus, impaired GADD34 expression reduces client protein load and ER stress in CHOP-/- cells exposed to perturbations that impair ER function. CHOP-/- and GADD34 mutant cells accumulate less high molecular weight protein complexes in their stressed ER than wild-type cells. Furthermore, mice lacking GADD34-directed eIF2 dephosphorylation, like CHOP-/- mice, are resistant to renal toxicity of the ER stress-inducing drug tunicamycin. CHOP also activates ERO1, which encodes an ER oxidase. Consequently, the ER of stressed CHOP-/- cells is relatively hypo-oxidizing. Pharmacological and genetic manipulations that promote a hypo-oxidizing ER reduce abnormal high molecular weight protein complexes in the stressed ER and protect from the lethal consequences of ER stress. CHOP deletion thus protects cells from ER stress by decreasing ER client protein load and changing redox conditions within the organelle.
[Keywords: Protein folding; chaperones; membranes; secretion; protein phosphorylation; gene expression]
Received August 17, 2004; revised version accepted October 14, 2004.
Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1250704.
3 Corresponding author.
E-MAIL ron{at}saturn.med.nyu.edu; FAX (212) 263-8951.
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