title: Transnitrosylation of XIAP regulates caspase-dependent neuronal cell death.
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 insights into the regulation of caspase activation in neurodegenerative disorders mediated, at least in part, by nitrosative stress.
authors.affiliation: 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.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Catherine C L
authors.initials: CC
authors.lastname: Wong
authors.forename: Fiona L
authors.initials: FL
authors.lastname: Scott
authors.forename: Brendan P
authors.initials: BP
authors.lastname: Eckelman
authors.forename: Xuemei
authors.initials: X
authors.lastname: Han
authors.forename: Christos
authors.initials: C
authors.lastname: Tzitzilonis
authors.forename: Fanjun
authors.initials: F
authors.lastname: Meng
authors.forename: Zezong
authors.initials: Z
authors.lastname: Gu
authors.forename: Emily A
authors.initials: EA
authors.lastname: Holland
authors.forename: Arjay T
authors.initials: AT
authors.lastname: Clemente
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Okamoto
authors.forename: Guy S
authors.initials: GS
authors.lastname: Salvesen
authors.forename: Roland
authors.initials: R
authors.lastname: Riek
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D009569:Nitric Oxide; D044767:Ubiquitin-Protein Ligases; D020169:Caspases