Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α‐mediated stress signaling

• Celio XC Santos ^[1] ; Anne D Hafstad ^[6] ; Matteo Beretta ^[1] ; Min Zhang ^[1] ; Chris Molenaar ^[1] ; Jola Kopec ^[3] ; Dina Fotinou ^[3] ; Thomas V Murray ^[1] ; Andrew M Cobb ^[1] ; Daniel Martin ^[1] ; Maira Zeh Silva ^[3] ; Narayana Anilkumar ^[1] ; Katrin Schröder ^[4] ; Catherine M Shanahan ^[1] ; Alison C Brewer ^[1] ; Ralf P Brandes ^[4] ; Eric Blanc ^[1] ; Maddy Parsons ^[5] ; Vsevelod Belousov ^[2] ; Richard Cammack ^[1] ; Robert C Hider ^[1] ; Roberto A Steiner ^[5] ; Ajay M Shah ^[1]
  1. [1] King's College London

     King's College London

     Reino Unido

     
  2. [2] Institute of Bioorganic Chemistry

     Institute of Bioorganic Chemistry

     Rusia

     
  3. [3] 1 Cardiovascular Division King's College London British Heart Foundation Centre of Excellence London UK; 3 Randall Division King's College London British Heart Foundation Centre of Excellence London UK
  4. [4] 4 Institute for Cardiovascular Physiology Goethe‐University Frankfurt Germany
  5. [5] 3 Randall Division King's College London British Heart Foundation Centre of Excellence London UK
  6. [6] 1 Cardiovascular Division King's College London British Heart Foundation Centre of Excellence London UK; 2 Cardiovascular Research Group Department of Medical Biology The Arctic University of Norway Tromsø Norway

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 35, Nº. 3, 2016, págs. 319-334
• Idioma: inglés
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  • 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.