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J. Biol. Chem., Vol. 278, Issue 26, 23376-23380, June 27, 2003

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Caspase-1 and Caspase-8 Cleave and Inactivate Cellular Parkin^*

Søren Kahns  , Michael Kalai  ¶, Lene Diness Jakobsen ||, Brian F. C. Clark , Peter Vandenabeele ¶ and Poul Henning Jensen || **

From the Department of Molecular Biology, University of Aarhus, DK-8000 Aarhus-C, Denmark, ^||Department of Medical Biochemistry, University of Aarhus, DK-8000 Aarhus-C, Denmark, and ^¶Molecular Signaling and Cell Death Unit, Department of Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology, Gent University, K. L. Ledeganckstraat 35, B-9000 Gent, Belgium

Lesions in the parkin gene cause early onset Parkinson's disease by a loss of dopaminergic neurons, thus demonstrating a vital role for parkin in the survival of these neurons. Parkin is inactivated by caspase cleavage, and the major cleavage site is after Asp¹²⁶. Caspases responsible for parkin cleavage were identified by several experimental paradigms. Transient coexpression of caspases and wild type parkin in HEK-293 cells identified caspase-1, -3, and -8 as efficient inducers of parkin cleavage whereas caspase-2, -7, -9, and -11 did not induce cleavage. A D126A parkin mutation abrogates cleavage induced by caspase-1 and -8, but not by caspase-3. In anti-Fas-treated Jurkat T cells, parkin cleavage was inhibited by caspase inhibitors hFlip and CrmA (but not by X-linked inhibitor of apoptosis (XIAP)), indicating that caspase-8 (but not caspase-3) is responsible for the parkin cleavage in this model. Moreover, induction of apoptosis in caspase-3-deficient MCF7 cells, either by caspase-1 or -8 overexpression or by tumor necrosis factor- treatment, led to parkin cleavage. These results demonstrate that caspase-1 and -8 can directly cleave parkin and suggest that death receptor activation and inflammatory stress can cause loss of the ubiquitin ligase activity of parkin, thus causing accumulation of toxic parkin substrates and triggering dopaminergic cell death.

Received for publication, January 16, 2003 , and in revised form, April 10, 2003.

^* This study was supported by Danish Medical Research Grant 9902995, 5th Frame Work Program Grant Protage QLK6-CT-1999-02193, The Lundbeck Foundation, The Aarhus University Research Foundation, and The Danish Parkinson Foundation. The work in the MSCDU was supported in part by the Interuniversitaire Attractiepolen V, the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (Grant 3G.0006.01 and Grant 3G.021199), EC-RTD Grant QLG1-CT-1999-00739, a RUG-cofinanciering EU Project (011C0300), and a RUG-GOA Project (12050502). 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.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed. Tel.: 45-8942-2856; Fax: 45-8613-1160; E-mail: phj{at}biokemi.au.dk.

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