Caspase-1 and caspase-8 cleave and inactivate cellular parkin.
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-alpha 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.
Kahns
Soren
S
Department of Molecular Biology, University of Aarhus, DK-8000 Aarhus-C, Denmark.
Kalai
Michael
M
Jakobsen
Lene Diness
LD
Clark
Brian F C
BF
Vandenabeele
Peter
P
Jensen
Poul Henning
PH
D017209:Apoptosis; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000032:analysis; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases; D019014:fas Receptor / Q000378:metabolism
D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D020170:Caspase 1; D008025:Ligases