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Published online 2 April 2001. doi:10.1083/jcb.153.1.221
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© The Rockefeller University Press, 0021-9525/2001//221 $5.00
The Journal of Cell Biology, Volume 153, Number 1, , 2001 221-228

Report

The Inhibitor of Apoptosis Protein-Binding Domain of Smac Is Not Essential for Its Proapoptotic Activity



Darren L. Robertsa, Wendy Merrisona, Marion MacFarlanea, and Gerald M. Cohena

a Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom
MRC Toxicology Unit, Hodgkin Bldg., University of Leicester, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK.44-116-252-561644-116-252-5553

mm21{at}le.ac.uk

Smac/DIABLO, a recently identified inhibitor of apoptosis protein (IAP)-binding protein, is released from the mitochondria during apoptosis and reportedly potentiates apoptosis by relieving the inhibition of IAPs on caspases. We now describe the molecular characterization of Smac β, an alternatively spliced form of Smac, which lacks the mitochondrial-targeting sequence found in Smac and has a cortical distribution in both human embryonic kidney 293 and breast epithelial tumor MCF-7 cells. Smac β, which binds IAPs in vitro, does not bind IAPs in intact cells due to cellular processing and removal of its NH2-terminal IAP-binding domain. Despite its inability to interact with IAPs in cells, processed Smac β is proapoptotic, as demonstrated by its ability to potentiate apoptosis induced by both death receptor and chemical stimuli. Furthermore, expression of a NH2-terminally truncated Smac mutant ({Delta}75), which lacks the entire IAP-interacting domain, potentiates apoptosis to the same extent as Smac and Smac β. Our data support the hypothesis that the main proapoptotic function of Smac and Smac β is due to a mechanism other than IAP binding.

Key Words: TRAIL • XIAP • alternative splicing • MCF-7 cells • mitochondria

© 2001 The Rockefeller University Press

Abbreviations used in this paper: HSV, herpes simplex virus ; IAP, inhibitor of apoptosis protein; MG132, carbobenzoxyl-leucinyl-leucinyl-leucinal; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand; XIAP, X-linked IAP.


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