TY  - JOUR
A1  - Santos, Celio X. C.
A1  - Hafstad, Anne D.
A1  - Beretta, Matteo
A1  - Zhang, Min
A1  - Molenaar, Chris
A1  - Kopec, Jola
A1  - Fotinou, Dina
A1  - Murray, Thomas V.
A1  - Cobb, Andrew M.
A1  - Martin, Daniel
A1  - Silva, Maira Zeh
A1  - Anilkumar, Narayana
A1  - Schröder, Katrin
A1  - Shanahan, Catherine M.
A1  - Brewer, Alison C.
A1  - Brandes, Ralf
A1  - Blanc, Eric
A1  - Parsons, Maddy
A1  - Belousov, Vsevelod
A1  - Cammack, Richard
A1  - Hider, Robert C.
A1  - Steiner, Roberto A.
A1  - Shah, Ajay M.
T1  - Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α‐mediated stress signaling
T2  - The EMBO Journal
N2  - 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.
Y1  - 2016
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/42513
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-425131
SN  - 1460-2075
N1  - This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
VL  - 35
IS  - 3
SP  - 319
EP  - 334
PB  - EMBO Press
CY  - Heidelberg
ER  -