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J. Biol. Chem., Vol. 282, Issue 34, 25088-25099, August 24, 2007

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Binding of Caspase-3 Prodomain to Heat Shock Protein 27 Regulates Monocyte Apoptosis by Inhibiting Caspase-3 Proteolytic Activation^*

From the Heart and Lung Research Institute, Division of Pulmonary and Critical Care and Department of Molecular Genetics, The Ohio State University, Columbus, Ohio 43210

Caspase-3 is an essential executioner of apoptosis responsible for regulating many important cellular processes, among them the number of circulating monocytes, central players in the innate immune response. The activation of caspase-3 requires its processing from an inactive precursor. Here we show that the small heat shock protein 27 (Hsp27) associates with caspase-3 and protein-protein interaction experiments in vivo and with purified proteins demonstrate a direct interaction between Hsp27 and the amino-terminal prodomain of caspase-3. Using an in vitro caspase-3 activation assay, our results further establish that the interaction of Hsp27 with the caspase-3 prodomain inhibits the second proteolytic cleavage necessary for caspase-3 activation, revealing a novel mechanism for the regulation of this effector caspase. Hsp27 expression in monocytes is constitutive. Consistent with a central role of Hsp27 in blocking caspase-3 activation, Hsp27 down-regulation by double-stranded RNA interference induces apoptosis of macrophages, whereas Hsp27 overexpression increases the life span of monocytes by inhibiting apoptosis. Highlighting the importance of cell partitioning in the regulation of apoptosis, immunofluorescence, and subcellular fractionation studies revealed that whereas both caspase-3 and Hsp27 are cytoplasmic in fresh monocytes (i.e. not undergoing apoptosis), Hsp27 moves to the nucleus during apoptosis, a relocalization that can be blocked by promoting the differentiation of monocytes to macrophages or by inhibiting cell death. These results reveal a novel mechanism of caspase-3 regulation and underscore a novel and fundamental role of Hsp27 in the regulation of monocyte life span.

Received for publication, February 28, 2007 , and in revised form, June 26, 2007.

^* This work is supported by American Cancer Society Grant IRG98-278-01, Grant RO1HL075040, and National Science Foundation Grant MCB-0542244 (to A. I. D.) and American Heart Association-Ohio Predoctoral Fellowship 0615290B (to O. H. V.). 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.

¹ These authors contributed equally.

² Present address: Dept. Pharmacology and Toxicology, School of Medicine, University of Alabama, Birmingham, AL 35294.

³ To whom correspondence should be addressed: 201 Heart and Lung Research Institute, Dept. Molecular Genetics. Div. Pulmonary and Critical Care. The Ohio State University, 473 West 12th Ave., Columbus, OH 43210. Tel.: 614-292-9507; Fax: 614-292-7778; E-mail: doseff.1{at}osu.edu.

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