Department of Molecular Medicine and Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, California, USA.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Antioxid Redox Signal. 2021 Sep 1;35(7):531-550. doi: 10.1089/ars.2021.0081. Epub 2021 Jun 21.
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 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]). Emerging evidence suggests that S-nitrosylation occurs predominantly 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. 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. We discuss future areas of study of protein transnitrosylation that link our understanding of aging, inflammation, and neurodegenerative diseases. 35, 531-550.
生理浓度的一氧化氮 (NO) 和相关的活性氮物种 (RNS) 介导神经系统中的多种信号通路。在炎症老化（与衰老相关的慢性低度炎症）和神经退行性疾病中，过量的 RNS 导致突触和神经元丧失。“NO 信号转导”在健康和疾病中主要通过蛋白质 S-亚硝基化（SNO）介导，这是一种基于氧化还原的翻译后修饰，其中“NO”（可能以亚硝酰阳离子[NO]的形式）与半胱氨酸巯基（或更准确地说，硫醇阴离子 [R-S]）反应。新出现的证据表明，S-亚硝基化主要发生在转亚硝基化（transnitrosylation）中。从机制上讲，该反应涉及硫醇阴离子作为亲核试剂，对亚硝基氮进行可逆亲核攻击，形成 SNO-蛋白质加合物。先前的研究确定了甘油醛-3-磷酸脱氢酶 (GAPDH)-核蛋白、硫氧还蛋白-半胱天冬酶-3 和 X 连锁凋亡抑制剂 (XIAP)-半胱天冬酶-3 之间的转亚硝基化反应。最近，我们发现，先前认为在完全不同的生化途径中起作用的酶在炎症老化过程中可以以意想不到的方式相互转亚硝基化，从而介导神经退行性变。因此，我们报道了一个来自 Uch-L1 到 Cdk5 到 Drp1 的协同三组分转亚硝基化网络，该网络介导阿尔茨海默病中的突触损伤。转亚硝基化代表了一种关键的化学机制，可将氧化还原介导的事件转导到不同的蛋白质亚群。尽管有成千上万的含巯基蛋白质发生 S-亚硝基化，但转亚硝基化如何调节众多神经元属性才刚刚开始被揭示。在这篇综述中，我们强调了蛋白质之间转亚硝基化作为疾病机制的化学生物学的最新进展。我们讨论了未来蛋白质转亚硝基化的研究领域，这些领域将我们对衰老、炎症和神经退行性疾病的理解联系起来。35, 531-550。
