TRANSNITROSYLATION OF XIAP REGULATES CASPASE-DEPENDENT NEURONAL CELL DEATH

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 X连锁凋亡抑制因子(XIAP)是半胱氨酸天冬氨酸氨基转移酶(Caspase)的有效拮抗剂。XIAP还作为E3泛素连接酶发挥作用，以caspase为靶点进行降解。然而，控制XIAP活性的分子途径仍然不清楚。在这里，我们报道了一氧化氮(NO)与XIAP通过S-亚硝化其环域(形成SNO-XIAP)反应，从而抑制E3连接酶和抗细胞凋亡活性。NO介导的神经毒性和caspase激活与几种神经退行性疾病有关，包括阿尔茨海默病、帕金森病和亨廷顿病。我们在这些疾病患者的大脑中发现了显著的SNO-XIAP形成，这表明这种反应与神经元损伤的病因有关。相反，已知的是，半胱氨酸酶的S亚硝化可以抑制细胞的凋亡活性。出乎意料的是，我们发现SNO-caspase反硝酸酯(将其NO基团转移到XIAP上)，形成SNO-XIAP，从而促进细胞损伤和死亡。这些发现为至少部分由亚硝化应激介导的神经退行性疾病中caspase激活的调节提供了洞察力。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. X-linked inhibitor of apoptosis (XIAP) is a potent antagonist of caspase apoptotic activity. XIAP also functions as an E3 ubiquitin ligase, targeting caspases for degradation. However, molecular pathways controlling XIAP activities remain unclear. Here, we report that nitric oxide (NO) reacts with XIAP by S-nitrosylating its RING domain (forming SNO-XIAP), thereby inhibiting E3 ligase and antiapoptotic activity. NO-mediated neurotoxicity and caspase activation have been linked to several neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases. We find significant SNO-XIAP formation in brains of patients with these diseases, implicating this reaction in the etiology of neuronal damage. Conversely, S-nitrosylation of caspases is known to inhibit apoptotic activity. Unexpectedly, we find that SNO-caspase transnitrosylates (transfers its NO group) to XIAP, forming SNO-XIAP, and thus promotes cell injury and death. These findings provide insights into the regulation of caspase activation in neurodegenerative disorders mediated, at least in part, by nitrosative stress.