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Papers In Press, published online ahead of print April 11, 2003
Medical Biochemistry, University of Aarhus, Aarhus-C DK-8000
Corresponding Author: phj{at}biokemi.au.dk
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 Asp 126. Caspases responsible for parkin cleavage were identified by several experimental paradigms. Transient coexpression of caspases and wild type parkin in HEK293 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 cells, parkin cleavage was inhibited by caspase inhibitors hFlip and CrmA but not by 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 TNF-a 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 parkins ubiquitin ligase activity and thus cause accumulation of toxic parkin substrates and trigger dopaminergic cell death.
J. Biol. Chem, 10.1074/jbc.M300495200
Submitted on January 16, 2003
Revised on April 10, 2003
Accepted on April 11, 2003
Caspase-1 and caspase-8 cleave and inactivate cellular parkin
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