Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2{alpha}-mediated stress signaling

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.

Source: EMBO Journal - January 31, 2016 Category: Molecular Biology Authors: Santos, C. X., Hafstad, A. D., Beretta, M., Zhang, M., Molenaar, C., Kopec, J., Fotinou, D., Murray, T. V., Cobb, A. M., Martin, D., Zeh Silva, M., Anilkumar, N., Schröder, K., Shanahan, C. M., Brewer, A. C., Brandes, R. P., Blanc, E., Parsons, M. Tags: Autophagy & Cell Death, Signal Transduction, Structural Biology Articles Source Type: research