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.

中文翻译：

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一氧化氮介导的蛋白质稳态的氧化还原调节。

一氧化氮是一种通用的可扩散信号分子，其三种NO合酶（NOS）的生物合成在转录和翻译后水平，辅助因子的可用性和钙结合方面受到严格调节。高于正常水平的NO具有有益的保护作用，例如在心血管系统中，但也有助于炎症性疾病的病理生理以及神经系统的衰老和神经退行性变。效果特异性取决于NOS同工酶的功能和空间特异性，以及两个主要信号传导机制的双重性（i）激活可溶性鸟苷酸化酶（sGC）依赖的cGMP产生，以及（ii）氧化还原敏感的半胱氨酸的直接S-亚硝基化易感蛋白质。本综述概述了蛋白质稳态中S-亚硝基化的功能含义，并着重于两种NO靶蛋白，即70 kDa的热休克同源蛋白（Hsc70 / HSPA8）和遍在蛋白2连接酶（UBE2D），因为两者均被修饰功能上关键的半胱氨酸，是伴侣蛋白介导和辅助的自噬和蛋白酶体蛋白降解的关键调节剂。这些候选人的SNO修饰与蛋白质的积累和神经元细胞的衰老表型的采用有关，这表明蛋白质稳态机械的S-亚硝化会导致衰老现象。因为两者都在功能关键的半胱氨酸上进行了修饰，并且是伴侣蛋白介导和辅助的自噬和蛋白酶体蛋白质降解的关键调节剂。这些候选人的SNO修饰与蛋白质的积累和神经元细胞的衰老表型的采用有关，这表明蛋白质稳态机械的S-亚硝化会导致衰老现象。因为两者都在功能关键的半胱氨酸上进行了修饰，并且是伴侣蛋白介导和辅助的自噬和蛋白酶体蛋白质降解的关键调节剂。这些候选人的SNO修饰与蛋白质的积累和神经元细胞的衰老表型的采用有关，这表明蛋白质稳态机械的S-亚硝化会导致衰老现象。