Transnitrosylation of XIAP regulates caspase-dependent neuronal cell death.
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.
Nakamura
Tomohiro
T
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.
Wang
Lei
L
Wong
Catherine C L
CC
Scott
Fiona L
FL
Eckelman
Brendan P
BP
Han
Xuemei
X
Tzitzilonis
Christos
C
Meng
Fanjun
F
Gu
Zezong
Z
Holland
Emily A
EA
Clemente
Arjay T
AT
Okamoto
Shu-ichi
S
Salvesen
Guy S
GS
Riek
Roland
R
Yates
John R
JR
Lipton
Stuart A
SA
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*
D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D009569:Nitric Oxide; D044767:Ubiquitin-Protein Ligases; D020169:Caspases