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 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.
Lee
Andrea W
AW
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montréal, Québec H3T 1E2, Canada.
Champagne
Nathalie
N
Wang
Xiaojun
X
Su
Xiao-Dong
XD
Goodyer
Cynthia
C
Leblanc
Andrea C
AC
D017398:Alternative Splicing; D001921:Brain / Q000166:cytology / Q000201:enzymology; D053178:Caspase 6 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D020868:Gene Silencing; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000201:enzymology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
D020033:Protein Isoforms; D011498:Protein Precursors; D034741:RNA, Small Interfering; D053178:Caspase 6; D046988:Proteasome Endopeptidase Complex