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Published online 17 November 2003. doi:10.1083/jcb.200307130
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© The Rockefeller University Press, 0021-9525/2003/11/789 $8.00
The Journal of Cell Biology, Volume 163, Number 4, 789-799

Article

Critical function of endogenous XIAP in regulating caspase activation during sympathetic neuronal apoptosis



Patrick Ryan Potts1, Shweta Singh1, Malia Knezek1, Craig B. Thompson3,4 and Mohanish Deshmukh1,2

1 Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599
2 Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC 27599
3 Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104
4 Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104

Address correspondence to Mohanish Deshmukh, 7109E Neuroscience Research Building, Box 7250, 103 Mason Farm Rd., University of North Carolina, Chapel Hill, NC 27599. Tel.: (919) 843-6004. Fax: (919) 966-1050. email: mohanish{at}med.unc.edu

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.

Key Words: Smac; cytochrome c; nerve growth factor; IAP; neurons

P.R. Potts and S. Singh contributed equally to this work.

The online version of this article includes supplemental material.

Abbreviations used in this paper: cIAP, cellular inhibitor of apoptosis protein; CPTcAMP, 8-(4-chlorophenylthio)adenosine-3'-5'-cyclic monophosphate; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; H2O2, hydrogen peroxide; IAP, inhibitor of apoptosis protein; XIAP, X-linked IAP.


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