Alternatively Spliced Caspase-6B Isoform Inhibits the Activation of Caspase-6A

Caspase-6 (Casp6) is activated early in Alzheimer disease and involved in axonal degeneration, but the regulation of Casp6 activity has not been explored. Several alternatively spliced forms of caspases act as inhibitors of caspase activation. The CASP6 gene generates an alternatively spliced transc...

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Bibliographic Details
Published in:The Journal of biological chemistry 2010-10, Vol.285 (42), p.31974-31984
Main Authors: Lee, Andrea W., Champagne, Nathalie, Wang, Xiaojun, Su, Xiao-Dong, Goodyer, Cynthia, LeBlanc, Andrea C.
Format: Article
Language:English
Subjects:
Alternative Splicing
Alzheimer Disease
Brain - cytology
Brain - enzymology
Caspase
Caspase 6 - genetics
Caspase 6 - metabolism
Cell Biology
Cell Line
Enzyme Activation
Gene Silencing
Humans
Molecular Bases of Disease
Neuroblastoma
Neurodegeneration
Neuron
Neurons - cytology
Neurons - enzymology
Proteasome Endopeptidase Complex - metabolism
Protein Isoforms - genetics
Protein Isoforms - metabolism
Protein Precursors - genetics
Protein Precursors - metabolism
Protein Stability
RNA Splicing
RNA, Small Interfering - genetics
RNA, Small Interfering - metabolism
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Summary:Caspase-6 (Casp6) is activated early in Alzheimer disease and involved in axonal degeneration, but the regulation of Casp6 activity has not been explored. Several alternatively spliced forms of caspases act as inhibitors of caspase activation. The CASP6 gene generates an alternatively spliced transcript known as CASP6β in addition to the CASP6α that encodes pro-Casp6a. Here, we show that the CASP6β transcript and the pro-Casp6b protein are present in many cell lines, in primary human neurons, and in human brains. Unlike most other alternatively spliced caspase transcripts, pro-Casp6b contains a catalytic site. However, purified pro-Casp6b did not have caspase activity, nor did it inhibit already activated Casp6a. Pro-Casp6b prevented the proteolytic activation of pro-Casp6a in vitro and in cells. Pro-Casp6b interacts directly with pro-Casp6a. This work shows that pro-Casp6b is an inhibitor of pro-Casp6a activation. These results imply that pro-Casp6b could negatively regulate pro-Casp6a activation in neurons and prevent Casp6a-mediated axonal degeneration.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.152744