title: Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α-mediated stress signaling.
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.
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, UK.
authors.forename: Celio X C
authors.initials: CX
authors.lastname: Santos
authors.affiliation: 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.
authors.forename: Anne D
authors.initials: AD
authors.lastname: Hafstad
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, UK.
authors.forename: Matteo
authors.initials: M
authors.lastname: Beretta
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, UK.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Molenaar
authors.affiliation: 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.
authors.forename: Jola
authors.initials: J
authors.lastname: Kopec
authors.affiliation: 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.
authors.forename: Dina
authors.initials: D
authors.lastname: Fotinou
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, UK.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Murray
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, UK.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Cobb
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martin
authors.affiliation: 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.
authors.forename: Maira
authors.initials: M
authors.lastname: Zeh Silva
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, UK.
authors.forename: Narayana
authors.initials: N
authors.lastname: Anilkumar
authors.affiliation: Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schröder
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, UK.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Shanahan
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, UK.
authors.forename: Alison C
authors.initials: AC
authors.lastname: Brewer
authors.affiliation: Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany.
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, UK.
authors.forename: Eric
authors.initials: E
authors.lastname: Blanc
authors.affiliation: Randall Division, King's College London British Heart Foundation Centre of Excellence, London, UK.
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
authors.forename: Vsevelod
authors.initials: V
authors.lastname: Belousov
authors.affiliation: Institute of Pharmaceutical Science, King's College London, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Cammack
authors.affiliation: Institute of Pharmaceutical Science, King's College London, London, UK.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Hider
authors.affiliation: Randall Division, King's College London British Heart Foundation Centre of Excellence, London, UK.
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Steiner
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London, UK ajay.shah@kcl.ac.uk.
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
mesh_terms: D000818:Animals; D002460:Cell Line; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D006801:Humans; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D010084:Oxidation-Reduction; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D015398:Signal Transduction
chemical_list: D015852:Eukaryotic Initiation Factor-2; D017476:Receptors, Neuropeptide Y; C109491:neuropeptide Y4 receptor; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1
keywords: Nox4; eIF2α; metal center; protein phosphatase; redox signaling