Sarah L Ullevig1, Hong Seok Kim2, John D Short3, Sina Tavakoli4, Susan T Weintraub5,6, Kevin Downs7, Reto Asmis4,6,8. 1. 1 Department of Kinesiology, Health, and Nutrition, University of Texas at San Antonio , San Antonio, Texas. 2. 2 Department of Molecular Medicine, College of Medicine, Inha University , Incheon, Korea. 3. 3 Department of Pharmacology, University of Texas Health Science Center at San Antonio , San Antonio, Texas. 4. 4 Department of Radiology, University of Texas Health Science Center at San Antonio , San Antonio, Texas. 5. 5 Institutional Mass Spectrometry Core Laboratory, University of Texas Health Science Center at San Antonio , San Antonio, Texas. 6. 6 Department of Biochemistry, University of Texas Health Science Center at San Antonio , San Antonio, Texas. 7. 7 Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio , San Antonio, Texas. 8. 8 Department of Clinical Laboratory Sciences, University of Texas Health Science Center at San Antonio , San Antonio, Texas.
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.
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 atheroscleroticmice 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.
Authors: Hong Seok Kim; Sarah L Ullevig; Debora Zamora; Chi Fung Lee; Reto Asmis Journal: Proc Natl Acad Sci U S A Date: 2012-09-18 Impact factor: 11.205
Authors: Deepthi Menon; Ashlee Innes; Aaron J Oakley; Jane E Dahlstrom; Lora M Jensen; Anne Brüstle; Padmaja Tummala; Melissa Rooke; Marco G Casarotto; Jonathan B Baell; Nghi Nguyen; Yiyue Xie; Matthew Cuellar; Jessica Strasser; Jayme L Dahlin; Michael A Walters; Gaetan Burgio; Luke A J O'Neill; Philip G Board Journal: Sci Rep Date: 2017-12-19 Impact factor: 4.379
Authors: John D Short; Sina Tavakoli; Huynh Nga Nguyen; Ana Carrera; Chelbee Farnen; Laura A Cox; Reto Asmis Journal: Front Immunol Date: 2017-08-22 Impact factor: 7.561