CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum.

By S. Marciniak, Chi Y. Yun, S. Oyadomari, I. Novoa, Yuhong Zhang, Rivka Jungreis, K. Nagata, H. Harding, D. Ron. Genes & Development, 2004

2,010 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Epidemiology, Surgery

View Paper: https://www.semanticscholar.org/paper/15cb63f9815e3e941c267621f5b50748cf0239f2

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

1. R. Kaufman
2. J. Malhotra
3. D. Ron
4. Peter Walter
5. Afshin Samali
6. A. Gorman
7. I. Tabas
8. C. Hetz

In Epidemiology

1. R. Kaufman
2. J. Malhotra
3. John Calvin Reed
4. Afshin Samali
5. A. Gorman
6. Peter Walter
7. D. Ron
8. I. Tabas

In Surgery

1. R. Kaufman
2. J. Malhotra
3. D. Ron
4. Peter Walter
5. I. Tabas
6. John Calvin Reed
7. Shiyu Wang
8. Jun Wu

Citations in the corpus

• ER stress: Autophagy induction, inhibition and selection (2015, background): “In addition, increasing biosynthesis of ER client proteins is caused mainly by dephosphorylation of EIF2S1 proteins by PPP1 (protein phosphatase 1), and DDIT3 regulates that pathway by activating PPP1R15A/GADD34.”
• Endoplasmic reticulum stress signaling in disease. (2006, background): “Additionally, ATF4 induction activates genes of the ISR, including GADD34, which relieves translational attenuation, and ERO1 , which promotes oxidataive protein folding.”
• Mediators of endoplasmic reticulum stress‐induced apoptosis (2006, background): “Moreover, inhibition of eIF2 phosphatases (with salubrinal) has been reported to reduce ER stress-induced apoptosis (Boyce et al, 2005; Marciniak et al, 2004).”
• Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities (2008, background): “In this regard, CHOP can exacerbate ER stress by inducing expression of genes encoding ER client proteins (thereby increasing protein load), and by rendering the ER more oxidative by inducing expression of the oxidase ERO1&alpha”
• Endoplasmic Reticulum Stress in Liver Disease (2010, background): “CHOP transcriptionally enhances the expression of GADD34, with subsequent dephosphorylation of eIF2a [90].”
• From acute ER stress to physiological roles of the Unfolded Protein Response (2006, background): “On the other hand, developmental or metabolic defects were not observed in mice with homozygous GADD34 mutation to prevent regulated peIF2a dephosphorylation.(81) The divergence between the gadd34- and p58-deleted mice may indicate that these two negative regulators play different physiological role”
• Endoplasmic Reticulum Stress and Oxidative Stress: A Vicious Cycle or a Double-Edged Sword? (2007, neutral): “:3) pathway can prevent oxidative stress through inhibition of translation initiation when protein folding in the ER lumen is disturbed (82).”
• The integrated stress response (2016, neutral): “This is achieved through dephosphorylation of eIF2 a by the phosphatase GADD34, which is induced by ATF4 and its downstream targets CHOP and ATF3 [15,78,79,166].”
• The endoplasmic reticulum and the unfolded protein response. (2007, background): “ERO1 encodes an ER oxidase that increases the oxidizing potential of the ER [63].”