期刊
ANTIOXIDANTS & REDOX SIGNALING
卷 35, 期 7, 页码 531-550出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2021.0081
关键词
S-nitrosylation; transnitrosylation; neurodegenerative diseases; nitric oxide
资金
- NIH [RF1 AG057409, R01 DA048882, R01 NS086890, P30 NS076411, P01 ES016738, DP1 DA041722, R01 AG056259, R01 AG061845]
- California Tobacco-Related Disease Research Program [TDRP 27IR-0010]
- Brain & Behavior Research Foundation
- Alzheimer's Association
- Michael J. Fox Foundation
- Step Family Foundation
Physiological concentrations of nitric oxide and related reactive nitrogen species play important roles in mediating signaling pathways in the nervous system. S-nitrosylation, particularly through transnitrosylation, is a critical chemical mechanism for transduction of redox-mediated events. Future studies should focus on understanding how transnitrosylation regulates various neuronal attributes in aging, inflammation, and neurodegenerative diseases.
Significance: Physiological concentrations of nitric oxide (NO center dot) and related reactive nitrogen species (RNS) mediate multiple signaling pathways in the nervous system. During inflammaging (chronic low-grade inflammation associated with aging) and in neurodegenerative diseases, excessive RNS contribute to synaptic and neuronal loss. NO signaling in both health and disease is largely mediated through protein S-nitrosylation (SNO), a redox-based posttranslational modification with NO (possibly in the form of nitrosonium cation [NO+]) reacting with cysteine thiol (or, more properly, thiolate anion [R-S-]). Recent Advances: Emerging evidence suggests that S-nitrosylation occurs predominantly via transnitros(yl)ation. Mechanistically, the reaction involves thiolate anion, as a nucleophile, performing a reversible nucleophilic attack on a nitroso nitrogen to form an SNO-protein adduct. Prior studies identified transnitrosylation reactions between glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-nuclear proteins, thioredoxin-caspase-3, and X-linked inhibitor of apoptosis (XIAP)-caspase-3. Recently, we discovered that enzymes previously thought to act in completely disparate biochemical pathways can transnitrosylate one another during inflammaging in an unexpected manner to mediate neurodegeneration. Accordingly, we reported a concerted tricomponent transnitrosylation network from Uch-L1-to-Cdk5-to-Drp1 that mediates synaptic damage in Alzheimer's disease. Critical Issues: Transnitrosylation represents a critical chemical mechanism for transduction of redox-mediated events to distinct subsets of proteins. Although thousands of thiol-containing proteins undergo S-nitrosylation, how transnitrosylation regulates a myriad of neuronal attributes is just now being uncovered. In this review, we highlight recent progress in the study of the chemical biology of transnitrosylation between proteins as a mechanism of disease. Future Directions: We discuss future areas of study of protein transnitrosylation that link our understanding of aging, inflammation, and neurodegenerative diseases.
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