Oxidative Post-Translational Modifications: A Focus on Cysteine S- Sulfhydration and the Regulation of Endothelial Fitness

Abstract

Significance: Changes in the oxidative balance can affect cellular physiology and adaptation through redox signaling. The endothelial cells that line blood vessels are particularly sensitive to reactive oxygen species, which can alter cell function by a number of mechanisms, including the oxidative post-translational modification (oxPTM) of proteins on critical cysteine thiols. Such modifications can act as redox-switches to alter the function of targeted proteins. Recent Advances: Mapping the cysteine oxPTM proteome and characterizing the effects of individual oxPTMs to gain insight into consequences for cellular responses has proven challenging. A recent addition to the list of reversible oxPTMs that contributes to cellular redox homeostasis is persulfidation or S-sulfhydration. Critical Issues: It has been estimated that up to 25% of proteins are S-sulfhydrated, making this modification almost as abundant as phosphorylation. In the endothelium, persulfides are generated by the trans-sulfuration pathway that catabolizes cysteine and cystathionine to generate hydrogen sulfide (H₂S) and H₂S-related sulfane sulfur compounds (H₂S_n). This pathway is of particular importance for the vascular system, as the enzyme cystathionine γ lyase (CSE) in endothelial cells accounts for a significant portion of total vascular H₂S/H₂S_n production. Future Directions: Impaired CSE activity in endothelial dysfunction has been linked with marked changes in the endothelial cell S-sulfhydrome and can contribute to the development of atherosclerosis and hypertension. It will be interesting to determine how changes in the S-sulfhydration of specific networks of proteins contribute to endothelial cell physiology and pathophysiology. Antioxid. Redox Signal. 35, 1494-1514.

Keywords: cysteine metabolism; hydrogen sulfide; oxidative post-translational modification; persulfidation.