CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum
AUTOR(ES)
Marciniak, Stefan J.
FONTE
Cold Spring Harbor Laboratory Press
RESUMO
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 α-subunit of translation initiation factor 2 (eIF2α) 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 eIF2α dephosphorylation, like CHOP-/- mice, are resistant to renal toxicity of the ER stress-inducing drug tunicamycin. CHOP also activates ERO1α, 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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=535917Documentos Relacionados
- Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153).
- CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum
- The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells*
- Targeted disruption of the Chop gene delays endoplasmic reticulum stress–mediated diabetes
- The unfolded protein response coordinates the production of endoplasmic reticulum protein and endoplasmic reticulum membrane.