Defective protein repair under methionine sulfoxide A deletion drives autophagy and ARE-dependent gene transcription

Steven M Pennington; Paula R Klutho; Litao Xie; Kim Broadhurst; Olha M Koval; Michael L McCormick; Douglas R Spitz; Isabella M Grumbach

doi:10.1016/j.redox.2018.04.001

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Defective protein repair under methionine sulfoxide A deletion drives autophagy and ARE-dependent gene transcription

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Defective protein repair under methionine sulfoxide A deletion drives autophagy and ARE-dependent gene transcription

Steven M Pennington, Paula R Klutho, Litao Xie, Kim Broadhurst, Olha M Koval, Michael L McCormick, Douglas R Spitz and Isabella M Grumbach

Redox biology, Vol.16, pp.401-413

06/2018

DOI: 10.1016/j.redox.2018.04.001

PMCID: PMC5953240

PMID: 29649787

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Abstract

Reduction of oxidized methionines is emerging as a major protein repair pathway. The lack of methionine sulfoxide reductase A (MsrA) exacerbates cardiovascular disease phenotypes driven by increased oxidative stress. However, the role of MsrA on maintaining cellular homeostasis in the absence of excessive oxidative stress is less well understood. Constitutive genetic deletion of MsrA increased formation of p62-containing protein aggregates, activated autophagy, and decreased a marker of apoptosis in vascular smooth muscle cells (VSMC). The association of Keap1 with p62 was augmented in MsrA-/- VSMC. Keap1 targets the transcription factor Nrf2, which regulates antioxidant genes, for proteasomal degradation. However, in MsrA-/- VSMC, the association of Nrf2 with Keap1 was diminished. Whereas Nrf2 mRNA levels were not decreased in MsrA-/- VSMC, we detected decreased ubiquitination of Nrf2 and a corresponding increase in total Nrf2 protein in the absence of biochemical markers of oxidative stress. Moreover, nuclear-localized Nrf2 was increased under MsrA deficiency, resulting in upregulation of Nrf2-dependent transcriptional activity. Consequently, transcription, protein levels and enzymatic activity of glutamate-cysteine ligase and glutathione reductase were greatly augmented in MsrA-/- VSMC. Our findings demonstrate that reversal of methionine oxidation is required for maintenance of cellular homeostasis in the absence of increased oxidative stress. These data provide the first link between autophagy and activation of Nrf2 in the setting of MsrA deletion. [Display omitted] •With MsrA deletion, p62-containing intracellular protein aggregates are increased.•Autophagy is increased in proliferating MsrA-/- smooth muscle cells.•Increased association of Keap-1 with p62 derepresses Nrf2 in MsrA-/- cells.•Nrf2 activation in MsrA-/- cells occurs without increased oxidative stress.

Methionine sulfoxide reductase

Smooth muscle

Ubiquitination

Nrf2

Autophagy

Methionine

Details

Title: Subtitle: Defective protein repair under methionine sulfoxide A deletion drives autophagy and ARE-dependent gene transcription
Creators: Steven M Pennington - Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Paula R Klutho - Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Litao Xie - Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Kim Broadhurst - Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Olha M Koval - Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Michael L McCormick - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
Douglas R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
Isabella M Grumbach - Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Redox biology, Vol.16, pp.401-413
DOI: 10.1016/j.redox.2018.04.001
PMID: 29649787
PMCID: PMC5953240
NLM abbreviation: Redox Biol
ISSN: 2213-2317
eISSN: 2213-2317
Publisher: Elsevier B.V
Grant note: name: Merit Review Grants, award: I01 BX000163; name: NIH, award: R01 HL 108932, R01 CA182804, P30 CA086862, T32 HL007121; DOI: 10.13039/100000968, name: American Heart Association, award: 14POST19860006
Language: English
Date published: 06/2018
Academic Unit: Pathology; Cardiovascular Medicine; Radiation Oncology; Chemistry; Internal Medicine
Record Identifier: 9984047988102771

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