CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum.
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 alpha-subunit of translation initiation factor 2 (eIF2alpha) 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 eIF2alpha dephosphorylation, like CHOP(-/-) mice, are resistant to renal toxicity of the ER stress-inducing drug tunicamycin. CHOP also activates ERO1alpha, 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.
Marciniak
Stefan J
SJ
Skirball Institute of Biomolecular Medicine, Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA.
Yun
Chi Y
CY
Oyadomari
Seiichi
S
Novoa
Isabel
I
Zhang
Yuhong
Y
Jungreis
Rivka
R
Nagata
Kazuhiro
K
Harding
Heather P
HP
Ron
David
D
D000704:Analysis of Variance; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D017173:Caenorhabditis elegans; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005347:Fibroblasts; D005786:Gene Expression Regulation; D015151:Immunoblotting; D047468:Immunoprecipitation; D007668:Kidney / Q000473:pathology; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D014176:Protein Biosynthesis / Q000502:physiology*; D054645:Protein Phosphatase 1; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology; D014415:Tunicamycin / Q000633:toxicity
D000943:Antigens, Differentiation; D022762:CCAAT-Enhancer-Binding Proteins; D018797:Cell Cycle Proteins; C497250:Ddit3 protein, mouse; D015852:Eukaryotic Initiation Factor-2; D009363:Neoplasm Proteins; D014157:Transcription Factors; D014415:Tunicamycin; D051742:Transcription Factor CHOP; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1