Protein Transnitrosylation Signaling Networks Contribute to Inflammaging and Neurodegenerative Disorders

This article was originally published here

Antioxid Redox Signal. 2021 May 6. doi: 10.1089/ars.2021.0081. Online ahead of print.


SIGNIFICANCE: Physiological concentrations of nitric oxide (NO•) 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 synapse and neuronal loss. ‘NO signaling’ in both health and disease is largely mediated through protein S-nitrosylation, 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 GAPDH-nuclear proteins, thioredoxin-caspase-3, and 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 fashion to mediate neurodegeneration. Accordingly, we reported a concerted tri-component 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.

PMID:33957758 | DOI:10.1089/ars.2021.0081