Nitric oxide mediated redox regulation of protein homeostasis.

Nitric oxide is a versatile diffusible signaling molecule, whose biosynthesis by three NO synthases (NOS) is tightly regulated at transcriptional and posttranslational levels, availability of co-factors, and calcium binding. Above normal levels of NO have beneficial protective effects for example in the cardiovascular system, but also contribute to the pathophysiology in the context of inflammatory diseases, and to aging and neurodegeneration in the nervous system. The effect specificity relies on the functional and spatial specificity of the NOS isoenzymes, and on the duality of two major signaling mechanisms (i) activation of soluble guanylycylase (sGC)-dependent cGMP production and (ii) direct S-nitrosylation of redox sensitive cysteines of susceptible proteins. The present review summarizes the functional implications of S-nitrosylation in the context of proteostasis, and focuses on two NO target proteins, heat shock cognate of 70 kDa (Hsc70/HSPA8) and the ubiquitin 2 ligase (UBE2D), because both are modified on functionally critical cysteines and are key regulators of chaperone mediated and assisted autophagy and proteasomal protein degradation. SNO modifications of these candidates are associated with protein accumulations and adoption of a senescent phenotype of neuronal cells suggesting that S-nitrosylations of protein homeostatic machineries contribute to aging phenomena.