Protein S-glutathionylation mediates macrophage responses to metabolic cues from the extracellular environment

Sarah L. Ullevig, Hong Seok Kim, John D. Short, Sina Tavakoli, Susan E Weintraub, Kevin Downs, Reto Asmis

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Aims: Protein S-glutathionylation, the formation of a mixed disulfide between glutathione and protein thiols, is an oxidative modification that has emerged as a new signaling paradigm, potentially linking oxidative stress to chronic inflammation associated with heart disease, diabetes, cancer, lung disease, and aging. Using a novel, highly sensitive, and selective proteomic approach to identify S-glutathionylated proteins, we tested the hypothesis that monocytes and macrophages sense changes in their microenvironment and respond to metabolic stress by altering their protein thiol S-glutathionylation status. Results: We identified over 130 S-glutathionylated proteins, which were associated with a variety of cellular functions, including metabolism, transcription and translation, protein folding, free radical scavenging, cell motility, and cell death. Over 90% of S-glutathionylated proteins identified in metabolically stressed THP-1 monocytes were also found in hydrogen peroxide (H2O2)-treated cells, suggesting that H2O2 mediates metabolic stress-induced protein S-glutathionylation in monocytes and macrophages. We validated our findings in mouse peritoneal macrophages isolated from both healthy and dyslipidemic atherosclerotic mice and found that 52% of the S-glutathionylated proteins found in THP-1 monocytes were also identified in vivo. Changes in macrophage protein S-glutathionylation induced by dyslipidemia were sexually dimorphic. Innovation: We provide a novel mechanistic link between metabolic (and thiol oxidative) stress, macrophage dysfunction, and chronic inflammatory diseases associated with metabolic disorders. Conclusion: Our data support the concept that changes in the extracellular metabolic microenvironment induce S-glutathionylation of proteins central to macrophage metabolism and a wide array of cellular signaling pathways and functions, which in turn initiate and promote functional and phenotypic changes in macrophages. Antioxid. Redox Signal. 25, 836-851.

Original languageEnglish (US)
Pages (from-to)836-851
Number of pages16
JournalAntioxidants and Redox Signaling
Volume25
Issue number15
DOIs
StatePublished - Nov 20 2016

Fingerprint

Macrophages
Protein S
Cues
Monocytes
Sulfhydryl Compounds
Oxidative stress
Physiological Stress
Metabolism
Oxidative Stress
Cell signaling
Protein folding
Pulmonary diseases
Scavenging
Cell death
Transcription
Glutathione Disulfide
Medical problems
Protein Folding
Peritoneal Macrophages
Disulfides

Keywords

  • atherosclerosis
  • macrophage
  • proteomics
  • S-glutathionylation
  • thiols

ASJC Scopus subject areas

  • Physiology
  • Biochemistry
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Protein S-glutathionylation mediates macrophage responses to metabolic cues from the extracellular environment. / Ullevig, Sarah L.; Kim, Hong Seok; Short, John D.; Tavakoli, Sina; Weintraub, Susan E; Downs, Kevin; Asmis, Reto.

In: Antioxidants and Redox Signaling, Vol. 25, No. 15, 20.11.2016, p. 836-851.

Research output: Contribution to journalArticle

Ullevig, Sarah L. ; Kim, Hong Seok ; Short, John D. ; Tavakoli, Sina ; Weintraub, Susan E ; Downs, Kevin ; Asmis, Reto. / Protein S-glutathionylation mediates macrophage responses to metabolic cues from the extracellular environment. In: Antioxidants and Redox Signaling. 2016 ; Vol. 25, No. 15. pp. 836-851.
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AB - Aims: Protein S-glutathionylation, the formation of a mixed disulfide between glutathione and protein thiols, is an oxidative modification that has emerged as a new signaling paradigm, potentially linking oxidative stress to chronic inflammation associated with heart disease, diabetes, cancer, lung disease, and aging. Using a novel, highly sensitive, and selective proteomic approach to identify S-glutathionylated proteins, we tested the hypothesis that monocytes and macrophages sense changes in their microenvironment and respond to metabolic stress by altering their protein thiol S-glutathionylation status. Results: We identified over 130 S-glutathionylated proteins, which were associated with a variety of cellular functions, including metabolism, transcription and translation, protein folding, free radical scavenging, cell motility, and cell death. Over 90% of S-glutathionylated proteins identified in metabolically stressed THP-1 monocytes were also found in hydrogen peroxide (H2O2)-treated cells, suggesting that H2O2 mediates metabolic stress-induced protein S-glutathionylation in monocytes and macrophages. We validated our findings in mouse peritoneal macrophages isolated from both healthy and dyslipidemic atherosclerotic mice and found that 52% of the S-glutathionylated proteins found in THP-1 monocytes were also identified in vivo. Changes in macrophage protein S-glutathionylation induced by dyslipidemia were sexually dimorphic. Innovation: We provide a novel mechanistic link between metabolic (and thiol oxidative) stress, macrophage dysfunction, and chronic inflammatory diseases associated with metabolic disorders. Conclusion: Our data support the concept that changes in the extracellular metabolic microenvironment induce S-glutathionylation of proteins central to macrophage metabolism and a wide array of cellular signaling pathways and functions, which in turn initiate and promote functional and phenotypic changes in macrophages. Antioxid. Redox Signal. 25, 836-851.

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