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

Celio Xc Santos; Anne D. Hafstad; Matteo Beretta; Min Zhang; Chris Molenaar; Jola Kopec; Dina Fotinou; Thomas V. Murray; Andrew M. Cobb; Daniel Martin; Maira Zeh Silva; Narayana Anilkumar; Katrin Schröder; Catherine M. Shanahan; Alison Brewer; Ralf P. Brandes; Eric Blanc; Maddy Parsons; Vsevelod Belousov; Richard Cammack; Robert C. Hider; Roberto A. Steiner; Ajay M. Shah

doi:10.15252/embj.201592394

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

Celio Xc Santos, Anne D. Hafstad, Matteo Beretta, Min Zhang, Chris Molenaar, Jola Kopec, Dina Fotinou, Thomas V. Murray, Andrew M. Cobb, Daniel Martin, Maira Zeh Silva, Narayana Anilkumar, Katrin Schröder, Catherine M. Shanahan, Alison Brewer, Ralf P. Brandes, Eric Blanc, Maddy Parsons, Vsevelod Belousov, Richard CammackRobert C. Hider, Roberto A. Steiner, Ajay M. Shah^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	319-334
Number of pages	16
Journal	The EMBO journal
Volume	35
Issue number	2
Early online date	18 Jan 2016
DOIs	https://doi.org/10.15252/embj.201592394
Publication status	Published - 1 Feb 2016

Keywords

eIF2α
Metal center
Nox4
Protein phosphatase
Redox signaling

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Santos, C. X., Hafstad, A. D., Beretta, M., Zhang, M., Molenaar, C., Kopec, J., Fotinou, D., Murray, T. V., Cobb, A. M., Martin, D., Zeh Silva, M., Anilkumar, N., Schröder, K., Shanahan, C. M., Brewer, A., Brandes, R. P., Blanc, E., Parsons, M., Belousov, V., ... Shah, A. M. (2016). Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α-mediated stress signaling. The EMBO journal, 35(2), 319-334. https://doi.org/10.15252/embj.201592394

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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.",

keywords = "eIF2α, Metal center, Nox4, Protein phosphatase, Redox signaling",

author = "Santos, {Celio Xc} and Hafstad, {Anne D.} and Matteo Beretta and Min Zhang and Chris Molenaar and Jola Kopec and Dina Fotinou and Murray, {Thomas V.} and Cobb, {Andrew M.} and Daniel Martin and {Zeh Silva}, Maira and Narayana Anilkumar and Katrin Schr{\"o}der and Shanahan, {Catherine M.} and Alison Brewer and Brandes, {Ralf P.} and Eric Blanc and Maddy Parsons and Vsevelod Belousov and Richard Cammack and Hider, {Robert C.} and Steiner, {Roberto A.} and Shah, {Ajay M.}",

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doi = "10.15252/embj.201592394",

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Santos, CX, Hafstad, AD, Beretta, M , Zhang, M, Molenaar, C, Kopec, J, Fotinou, D, Murray, TV , Cobb, AM , Martin, D, Zeh Silva, M, Anilkumar, N, Schröder, K, Shanahan, CM , Brewer, A, Brandes, RP, Blanc, E, Parsons, M, Belousov, V, Cammack, R , Hider, RC , Steiner, RA & Shah, AM 2016, 'Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α-mediated stress signaling', The EMBO journal, vol. 35, no. 2, pp. 319-334. https://doi.org/10.15252/embj.201592394

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T1 - Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α-mediated stress signaling

AU - Santos, Celio Xc

AU - Hafstad, Anne D.

AU - Beretta, Matteo

AU - Zhang, Min

AU - Molenaar, Chris

AU - Kopec, Jola

AU - Fotinou, Dina

AU - Murray, Thomas V.

AU - Cobb, Andrew M.

AU - Martin, Daniel

AU - Zeh Silva, Maira

AU - Anilkumar, Narayana

AU - Schröder, Katrin

AU - Shanahan, Catherine M.

AU - Brewer, Alison

AU - Brandes, Ralf P.

AU - Blanc, Eric

AU - Parsons, Maddy

AU - Belousov, Vsevelod

AU - Cammack, Richard

AU - Hider, Robert C.

AU - Steiner, Roberto A.

AU - Shah, Ajay M.

PY - 2016/2/1

Y1 - 2016/2/1

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.

AB - 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.

KW - eIF2α

KW - Metal center

KW - Nox4

KW - Protein phosphatase

KW - Redox signaling

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U2 - 10.15252/embj.201592394

DO - 10.15252/embj.201592394

M3 - Article

SN - 0261-4189

VL - 35

SP - 319

EP - 334

JO - The EMBO journal

JF - The EMBO journal

IS - 2

ER -

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

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