Back to Search
Start Over
Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α-mediated stress signaling.
- Source :
- EMBO Journal; 2/1/2016, Vol. 35 Issue 3, p319-334, 16p
- Publication Year :
- 2016
-
Abstract
- Phosphorylation of translation initiation factor 2α ( eIF2α) attenuates global protein synthesis but enhances translation of activating transcription factor 4 ( ATF4) and is a crucial evolutionarily conserved adaptive pathway during cellular stresses. The serine-threonine protein phosphatase 1 ( PP1) deactivates this pathway whereas prolonging eIF2α phosphorylation enhances cell survival. Here, we show that the reactive oxygen species-generating NADPH oxidase-4 (Nox4) is induced downstream of ATF4, binds to a PP1-targeting subunit GADD34 at the endoplasmic reticulum, and inhibits PP1 activity to increase eIF2α phosphorylation and ATF4 levels. Other PP1 targets distant from the endoplasmic reticulum are unaffected, indicating a spatially confined inhibition of the phosphatase. PP1 inhibition involves metal center oxidation rather than the thiol oxidation that underlies redox inhibition of protein tyrosine phosphatases. We show that this Nox4-regulated pathway robustly enhances cell survival and has a physiologic role in heart ischemia-reperfusion and acute kidney injury. This work uncovers a novel redox signaling pathway, involving Nox4- GADD34 interaction and a targeted oxidative inactivation of the PP1 metal center, that sustains eIF2α phosphorylation to protect tissues under stress. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02614189
- Volume :
- 35
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- EMBO Journal
- Publication Type :
- Academic Journal
- Accession number :
- 112732520
- Full Text :
- https://doi.org/10.15252/embj.201592394