TRANSNITROSYLATION OF XIAP REGULATES CASPASE-DEPENDENT NEURONAL CELL DEATH

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 X连锁凋亡抑制因子（XIAP）是一种强有力的caspase凋亡抑制剂。XIAP还作为E3泛素连接酶发挥作用，靶向半胱天冬酶进行降解。然而，控制XIAP活性的分子途径仍不清楚。在这里，我们报告说，一氧化氮（NO）与XIAP反应的S-亚硝基化其环域（形成SNO-XIAP），从而抑制E3连接酶和抗凋亡活性。NO介导的神经毒性和半胱天冬酶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。我们发现在这些疾病患者的大脑中有显著的SNO-XIAP形成，暗示这种反应与神经元损伤的病因有关。相反，已知半胱天冬酶的S-亚硝基化抑制凋亡活性。出乎意料的是，我们发现SNO-半胱天冬酶将其NO基团转移到XIAP，形成SNO-XIAP，从而促进细胞损伤和死亡。这些研究结果提供了深入的了解，在神经退行性疾病介导的半胱天冬酶激活的调节，至少部分，由亚硝化应激。

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.