1. Transnitrosylation of XIAP Regulates Caspase-Dependent Neuronal Cell Death
- Author
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Tomohiro Nakamura, John R. Yates, Brendan P. Eckelman, Guy S. Salvesen, Fanjun Meng, Christos Tzitzilonis, Xuemei Han, Lei Wang, Shu-ichi Okamoto, Roland Riek, Arjay Clemente, Stuart A. Lipton, Catherine C. L. Wong, Zezong Gu, Emily A. Holland, and Fiona L. Scott
- Subjects
Programmed cell death ,Ubiquitin-Protein Ligases ,Apoptosis ,X-Linked Inhibitor of Apoptosis Protein ,Nitric Oxide ,Inhibitor of apoptosis ,Article ,medicine ,Humans ,Molecular Biology ,Caspase ,biology ,Neurotoxicity ,Neurodegenerative Diseases ,Cell Biology ,medicine.disease ,Protein Structure, Tertiary ,Ubiquitin ligase ,XIAP ,Cell biology ,Enzyme Activation ,HtrA serine peptidase 2 ,Caspases ,biology.protein ,Protein Processing, Post-Translational - Abstract
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 unique insights into the regulation of caspase activation in neurodegenerative disorders mediated, at least in part, by nitrosative stress.
- Published
- 2010