Apoptosis‐associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl‐2

Apoptosis‐associated release of Smac/DIABLO from mitochondria requires active caspases and is... Smac/DIABLO is a mitochondrial protein that potentiates some forms of apoptosis, possibly by neutralizing one or more members of the IAP family of apoptosis inhibitory proteins. Smac has been shown to exit mitochondria and enter the cytosol during apoptosis triggered by UV‐ or γ‐irradiation. Here, we report that Smac/DIABLO export from mitochondria into the cytosol is provoked by cytotoxic drugs and DNA damage, as well as by ligation of the CD95 death receptor. Mitochondrial efflux of Smac/DIABLO, in response to a variety of pro‐apoptotic agents, was profoundly inhibited in Bcl‐2‐overexpressing cells. Thus, in addition to modulating apoptosis‐associated mitochondrial cytochrome c release, Bcl‐2 also regulates Smac release, suggesting that both molecules may escape via the same route. However, whereas cell stress‐associated mitochondrial cytochrome c release was largely caspase independent, release of Smac/DIABLO in response to the same stimuli was blocked by a broad‐spectrum caspase inhibitor. This suggests that apoptosis‐associated cytochrome c and Smac/DIABLO release from mitochondria do not occur via the same mechanism. Rather, Smac/DIABLO efflux from mitochondria is a caspase‐catalysed event that occurs downstream of cytochrome c release. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The EMBO Journal Wiley

Apoptosis‐associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl‐2

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Publisher
Wiley
Copyright
Copyright © 2013 Wiley Periodicals, Inc
ISSN
0261-4189
eISSN
1460-2075
D.O.I.
10.1093/emboj/20.23.6627
Publisher site
See Article on Publisher Site

Abstract

Smac/DIABLO is a mitochondrial protein that potentiates some forms of apoptosis, possibly by neutralizing one or more members of the IAP family of apoptosis inhibitory proteins. Smac has been shown to exit mitochondria and enter the cytosol during apoptosis triggered by UV‐ or γ‐irradiation. Here, we report that Smac/DIABLO export from mitochondria into the cytosol is provoked by cytotoxic drugs and DNA damage, as well as by ligation of the CD95 death receptor. Mitochondrial efflux of Smac/DIABLO, in response to a variety of pro‐apoptotic agents, was profoundly inhibited in Bcl‐2‐overexpressing cells. Thus, in addition to modulating apoptosis‐associated mitochondrial cytochrome c release, Bcl‐2 also regulates Smac release, suggesting that both molecules may escape via the same route. However, whereas cell stress‐associated mitochondrial cytochrome c release was largely caspase independent, release of Smac/DIABLO in response to the same stimuli was blocked by a broad‐spectrum caspase inhibitor. This suggests that apoptosis‐associated cytochrome c and Smac/DIABLO release from mitochondria do not occur via the same mechanism. Rather, Smac/DIABLO efflux from mitochondria is a caspase‐catalysed event that occurs downstream of cytochrome c release.

Journal

The EMBO JournalWiley

Published: Dec 3, 2001

References

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