| First Author | Santos CX | Year | 2016 |
| Journal | EMBO J | Volume | 35 |
| Issue | 3 | Pages | 319-34 |
| PubMed ID | 26742780 | Mgi Jnum | J:229931 |
| Mgi Id | MGI:5754909 | Doi | 10.15252/embj.201592394 |
| Citation | Santos CX, et al. (2016) Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2alpha-mediated stress signaling. EMBO J 35(3):319-34 |
| abstractText | Phosphorylation of translation initiation factor 2alpha (eIF2alpha) 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 eIF2alpha 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 eIF2alpha 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 eIF2alpha phosphorylation to protect tissues under stress. |
