Extended polyglutamine selectively interacts with caspase-8 and -10 in nuclear aggregates.
A growing number of inherited neurodegenerative disorders, including Huntington's disease, have been shown to be caused by the expansion of CAG/polyglutamine repeats. The molecular mechanism underlying these disorders, however, has yet to be clarified. We and others previously demonstrated that caspase-8 was activated by proteolysis in association with the expression of extended polyglutamine. Here, we further analyzed the selectivity of caspases in the process mediated by extended polyglutamine. Among upstream caspases, caspase-10, a close homolog of caspase-8, was also proteolytically activated, but caspase-9 was not. Caspase-8 and -10 were recruited into nuclear aggregates of extended polyglutamine, where at least a fraction of these caspases was converted to the activated forms. Caspase-8 and -10 were co-immunoprecipitated with polyglutamine only when the polyglutamine was pathologically extended, whereas caspase-2, -3, -6, -7 and -9 were not co-immunoprecipitated with polyglutamine regardless of its size. A dominant-negative form of caspase-8 with a mutation at the catalytic cysteine residue inhibited polyglutamine-mediated nuclear apoptotic phenotype. These results suggest that caspase-8 and -10 are autoactivated as a result of close proximity of the proforms of these molecules that occurs due to aggregate formation, which reveals a novel toxic gain-of-function mechanism for the pathogenesis of CAG-repeat disorders.
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M
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Department of Genetics, National Children's Medical Research Center, 3-35-31, Taishido, Setagaya, Tokyo 154-8509, Japan.
Miyashita
T
T
Ohtsuka
Y
Y
Okamura-Oho
Y
Y
Shikama
Y
Y
Yamada
M
M
D017209:Apoptosis; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure; D005455:Fluorescent Antibody Technique; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019169:Jurkat Cells; D018613:Microscopy, Confocal; D009154:Mutation; D010455:Peptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion; D014407:Tumor Cells, Cultured
D010455:Peptides; C097188:polyglutamine; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; C506438:CASP10 protein, human