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- Title
Oxidation of HRas cysteine thiols by metabolic stress prevents palmitoylation in vivo and contributes to endothelial cell apoptosis.
- Authors
Burgoyne, Joseph R.; Haeussler, Dagmar J.; Kumar, Vikas; Ji, Yuhan; Pimental, David R.; Zee, Rebecca S.; Costello, Cathrine E.; Cheng Lin; McComb, Mark E.; Cohen, Richard A.; Bachschmid, Markus M.
- Abstract
Here we demonstrate a new paradigm in redox signaling, whereby oxidants resulting from metabolic stress directly alter protein palmitoylation by oxidizing reactive cysteine thiolates. In mice fed a high-fat, high-sucrose diet and in cultured endothelial cells (ECs) treated with high palmitate and high glucose (HPHG), there was decreased HRas palmitoylation on Cys181/184 (61±24% decrease for cardiac tissue and 38±7.0% in ECs). This was due to oxidation of Cys181/184, detected using matrix-assisted laser desorption/ ionization time of flight (MALDI TOF)-TOF. Decrease in HRas palmitoylation affected its compartmentalization and Ras binding domain binding activity, with a shift from plasma membrane tethering to Golgi localization. Loss of plasma membrane-bound HRas decreased growth factor-stimulated ERK phosphorylation (84±8.6% decrease) and increased apoptotic signaling (24±6.5-fold increase) after HPHG treatment that was prevented by overexpressing wild-type but not C181/184S HRas. The essential role of HRas in metabolic stress was made evident by the similar effects of expressing an inactive dominant negative N17-HRas or a MEK inhibitor. Furthermore, the relevance of thiol oxidation was demonstrated by overexpressing manganese superoxide dismutase, which improved HRas palmitoylation and ERK phosphorylation, while lessening apoptosis in 0HPHG treated ECs.
- Subjects
OXIDIZING agents; PALMITOYLATION; CYSTEINE; THIOLATES; SUCROSE
- Publication
FASEB Journal, 2012, Vol 26, Issue 2, p832
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.11-189415