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J. Biol. Chem., Vol. 283, Issue 28, 19499-19510, July 11, 2008

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Caspase-8 Cleaves Histone Deacetylase 7 and Abolishes Its Transcription Repressor Function^*

Fiona L. Scott¹, Greg J. Fuchs, Sarah E. Boyd, Jean-Bernard Denault², Christine J. Hawkins^¶||, Franck Dequiedt^**, and Guy S. Salvesen

From the Program in Apoptosis and Cell Death Research, Burnham Institute for Medical Research, La Jolla, California 92037, Faculty of Information Technology, Monash University, Melbourne, Victoria 3800, Australia, the ^¶Department of Biochemistry, La Trobe University, Kingsbury Drive, Bundoora, Victoria 3086, Australia, ^||Children's Cancer Centre, Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Road, Parkville 3050, Victoria, Australia, and ^**Cellular and Molecular Biology Unit, Faculty of Agronomy, B-5030 Gembloux, Belgium

Caspase-8 is the initiator caspase of the extrinsic apoptosis pathway and also has a role in non-apoptotic physiologies. Identifying endogenous substrates for caspase-8 by using integrated bioinformatics and biological approaches is required to delineate the diverse roles of this caspase. We describe a number of novel putative caspase-8 substrates using the Prediction of Protease Specificity (PoPS) program, one of which is histone deacetylase 7 (HDAC7). HDAC7 is cleaved faster than any other caspase-8 substrate described to date. It is also cleaved in primary CD4⁺CD8⁺ thymocytes undergoing extrinsic apoptosis. By using naturally occurring caspase inhibitors that have evolved exquisite specificity at concentrations found within the cell, we could unequivocally assign the cleavage activity to caspase-8. Importantly, cleavage of HDAC7 alters its subcellular localization and abrogates its Nur77 repressor function. Thus we demonstrate a direct role for initiator caspase-mediated proteolysis in promoting gene transcription.

Received for publication, January 14, 2008 , and in revised form, April 16, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants RR20843 and CA69381. This work was also supported by Australian Research Council Grant DP0771183. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and additional references.

² Present address: University of Sherbrooke, Faculty of Medicine, Dept. of Pharmacology, 3001 13th Ave. North, Sherbrooke, Quebec J1H 5N4, Canada.

¹ To whom correspondence should be addressed: Program in Apoptosis and Cell Death Research, Burnham Institute for Medical Research, 10901 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-646-3100; Fax: 858-713-6274; E-mail: fscott{at}burnham.org.

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