Critical function of endogenous XIAP in regulating caspase activation during sympathetic neuronal apoptosis.
In sympathetic neurons, unlike most nonneuronal cells, growth factor withdrawal-induced apoptosis requires the development of competence in addition to cytochrome c release to activate caspases. Thus, although most nonneuronal cells die rapidly with cytosolic cytochrome c alone, sympathetic neurons are remarkably resistant unless they develop competence. We have identified endogenous X-linked inhibitor of apoptosis protein (XIAP) as the essential postcytochrome c regulator of caspase activation in these neurons. In contrast to wild-type neurons that are resistant to injection of cytochrome c, XIAP-deficient neurons died rapidly with cytosolic cytochrome c alone. Surprisingly, the release of endogenous Smac was not sufficient to overcome the XIAP resistance in sympathetic neurons. In contrast, the neuronal competence pathway permitted cytochrome c to activate caspases by inducing a marked reduction in XIAP levels in these neurons. Thus, the removal of XIAP inhibition appears both necessary and sufficient for cytochrome c to activate caspases in sympathetic neurons. These data identify a critical function of endogenous XIAP in regulating apoptosis in mammalian cells.
Potts
Patrick Ryan
PR
Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Singh
Shweta
S
Knezek
Malia
M
Thompson
Craig B
CB
Deshmukh
Mohanish
M
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D004789:Enzyme Activation / Q000502:physiology; D005728:Ganglia, Sympathetic / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein
D011506:Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D020169:Caspases