title: Sulfhydryl-mediated redox signaling in inflammation: role in neurodegenerative diseases.
abstract: Posttranslational modifications of cysteine sulfhydryl (-SH) moieties, e.g., S-nitrosylation, S-glutathionylation, or S-sulfuration, play an important role in cellular response to oxidative stress. Reversible cysteine modifications alter protein function and can play a critical role in redox signal transduction. Perturbation of sulfhydryl homeostasis is a hallmark of many diseases, including neurodegenerative disorders. Besides direct oxidative stress within the neurons, inflammation of the central nervous system as well as the periphery is implicated also in the development and progression of neurodegeneration. Therefore, perturbation of redox regulation of key inflammatory mediators is an important component of neurodegenerative diseases. Many proteins involved in inflammation have been shown to undergo S-nitrosylation (-SNO) and/or S-glutathionylation (-SSG) with functional consequences. The mechanistic and functional relationships between these two modifications have yet to be thoroughly investigated. While protein-SNO intermediates in some cases may signal independently of protein-SSG intermediates, the relatively unstable nature of protein-SNO derivatives in the presence of GSH suggests that protein-SNO formation in many cases may serve as a precursor for protein-SSG modifications. In this review, we describe the cysteine modifications of specific inflammation-mediating proteins and their relationship to inflammatory responses such as cytokine and chemokine production. In particular, we consider evidence for sequential protein-SNO → protein-SSG modifications of these proteins. We conclude that cysteine modifications of critical regulatory proteins are likely to play a central role in the onset and progression of neuroinflammatory diseases and thus should be studied thoroughly in this context.
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106-4965, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Gorelenkova Miller
authors.forename: John J
authors.initials: JJ
authors.lastname: Mieyal
mesh_terms: D000818:Animals; D003545:Cysteine / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D019636:Neurodegenerative Diseases / Q000503:physiopathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013438:Sulfhydryl Compounds / Q000737:chemistry
chemical_list: D011506:Proteins; D013438:Sulfhydryl Compounds; D003545:Cysteine