| Transnitrosylation of XIAP regulates caspase-dependent neuronal cell death. | |
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MedLine Citation:
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PMID: 20670888 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Tomohiro Nakamura; Lei Wang; Catherine C L Wong; Fiona L Scott; Brendan P Eckelman; Xuemei Han; Christos Tzitzilonis; Fanjun Meng; Zezong Gu; Emily A Holland; Arjay T Clemente; Shu-ichi Okamoto; Guy S Salvesen; Roland Riek; John R Yates; Stuart A Lipton |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Molecular cell Volume: 39 ISSN: 1097-4164 ISO Abbreviation: Mol. Cell Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-07-30 Completed Date: 2010-08-20 Revised Date: 2011-08-02 |
Medline Journal Info:
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Nlm Unique ID: 9802571 Medline TA: Mol Cell Country: United States |
Other Details:
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Languages: eng Pagination: 184-95 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis* Caspases / genetics, metabolism* Enzyme Activation / genetics Humans Neurodegenerative Diseases / genetics, metabolism Nitric Oxide / genetics, metabolism* Protein Processing, Post-Translational* Protein Structure, Tertiary Ubiquitin-Protein Ligases / genetics, metabolism X-Linked Inhibitor of Apoptosis Protein / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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P01 HD029587-16/HD/NICHD NIH HHS; P01 HD29587/HD/NICHD NIH HHS; P30 NS057096/NS/NINDS NIH HHS; P30 NS057096-05/NS/NINDS NIH HHS; R01 EY005477-26/EY/NEI NIH HHS; R01 EY009024-20/EY/NEI NIH HHS; R01 EY05477/EY/NEI NIH HHS; R01 EY09024/EY/NEI NIH HHS; R01 NS041207-02/NS/NINDS NIH HHS; R01 NS37878/NS/NINDS NIH HHS; R01 NS41207/NS/NINDS NIH HHS; T32 CA77109/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/X-Linked Inhibitor of Apoptosis Protein; 0/XIAP protein, human; 10102-43-9/Nitric Oxide; EC 3.4.22.-/Caspases; EC 6.3.2.19/Ubiquitin-Protein Ligases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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