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J. Biol. Chem., Vol. 283, Issue 27, 19140-19150, July 4, 2008

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Cysteine Cathepsins Trigger Caspase-dependent Cell Death through Cleavage of Bid and Antiapoptotic Bcl-2 Homologues^*

Gabriela Droga-Mazovec¹², Lea Boji¹, Ana Petelin¹, Saka Ivanova, Rok Romih, Urska Repnik, Guy S. Salvesen^¶, Veronika Stoka, Vito Turk, and Boris Turk³

From the Department of Biochemistry, Molecular and Structural Biology, J. Stefan Institute, Sl-1000 Ljubljana, Slovenia, the Institute of Cell Biology, University of Ljubljana Medical Faculty, Sl-1105 Ljubljana, Slovenia, and ^¶The Burnham Institute for Medical Research, La Jolla, California 92037

As a model for defining the role of lysosomal cathepsins in apoptosis, we characterized the action of the lysosomotropic agent LeuLeuOMe using distinct cellular models. LeuLeuOMe induces lysosomal membrane permeabilization, resulting in release of lysosomal cathepsins that cleave the proapoptotic Bcl-2 family member Bid and degrade the antiapoptotic member Bcl-2, Bcl-xL, or Mcl-1. The papain-like cysteine protease inhibitor E-64d largely prevented apoptosis, Bid cleavage, and Bcl-2/Bcl-xL/Mcl-1 degradation. The pancaspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(OMe)fluoromethyl ketone failed to prevent Bid cleavage and degradation of anti-apoptotic Bcl-2 homologues but substantially decreased cell death, suggesting that cathepsin-mediated apoptosis in these cellular models mostly follows a caspase-dependent pathway. Moreover, in vitro experiments showed that one or more of the cysteine cathepsins B, L, S, K, and H could cleave Bcl-2, Bcl-xL, Mcl-1, Bak, and BimEL, whereas no Bax cleavage was observed. On the basis of inhibitor studies, we demonstrate that lysosomal disruption triggered by LeuLeuOMe occurs before mitochondrial damage. We propose that degradation of anti-apoptotic Bcl-2 family members by lysosomal cathepsins synergizes with cathepsin-mediated activation of Bid to trigger a mitochondrial pathway to apoptosis. Moreover, XIAP (X-chromosome-linked inhibitor of apoptosis) was also found to be a target of cysteine cathepsins, suggesting that cathepsins can mediate caspase-dependent apoptosis also downstream of mitochondria.

Received for publication, April 1, 2008

^* This work was supported by Ministry of Higher Education, Science, and Technology of the Republic of Slovenia Grant P-0140 (to V. T.) and Human Frontier Science Program Grant RGP0024/2006-C (to B. T. and G. S.). 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 Figs. 1-7.

¹ These authors contributed equally to this work.

² Recipient of a fellowship from Ad-Futura (Slovenia).

³ To whom correspondence should be addressed. Tel.: 386-1-477-37-72; Fax: 386-1-477-3894; E-mail: boris.turk{at}ijs.si.

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