Premium
Apoptosis‐associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl‐2
Author(s) -
Adrain Colin,
Creagh Emma M.,
Martin Seamus J.
Publication year - 2001
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/20.23.6627
Subject(s) - cytochrome c , mitochondrion , apoptosis , biology , microbiology and biotechnology , caspase , cytosol , mitochondrial apoptosis induced channel , apoptosome , intrinsic apoptosis , programmed cell death , caspase 2 , caspase 9 , fas receptor , biochemistry , enzyme
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.