2. Academic Validation
  3. Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α-mediated stress signaling

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

  • EMBO J. 2016 Feb 1;35(3):319-34. doi: 10.15252/embj.201592394.
Celio X C Santos 1,  Anne D Hafstad 2,  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 5,  Maddy Parsons 6,  Vsevelod Belousov 7,  Richard Cammack 8,  Robert C Hider 8,  Roberto A Steiner 6,  Ajay M Shah 9
Affiliations

Affiliations

  • 1 Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, UK.
  • 2 Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, UK Cardiovascular Research Group, Department of Medical Biology, The Arctic University of Norway, Tromsø, Norway.
  • 3 Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, UK Randall Division, King's College London British Heart Foundation Centre of Excellence, London, UK.
  • 4 Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany.
  • 5 MRC Centre for Developmental Neurobiology, King's College London, London, UK.
  • 6 Randall Division, King's College London British Heart Foundation Centre of Excellence, London, UK.
  • 7 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
  • 8 Institute of Pharmaceutical Science, King's College London, London, UK.
  • 9 Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, UK ajay.shah@kcl.ac.uk.
PMID: 26742780 DOI: 10.15252/embj.201592394
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.

Keywords

Nox4; eIF2α; metal center; protein phosphatase; redox signaling.

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