A Caspase-9 Variant Missing the Catalytic Site Is an Endogenous Inhibitor of Apoptosis

It is likely that endogenous inhibitors of the apical caspases such as caspase-9 exist to prevent undesirable activation of caspase cascades. A naturally occurring variant of caspase-9 named caspase-9S was cloned from human liver. Caspase-9S is missing most of the large subunit of caspase-9, includi...

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Bibliographic Details
Published in:The Journal of biological chemistry 1999-01, Vol.274 (4), p.2072-2076
Main Authors: Seol, Dai-Wu, Billiar, Timothy R.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Apoptosis - physiology
Caspase 9
Caspases - genetics
Caspases - metabolism
Caspases - physiology
Catalytic Domain
Cell Line
Cloning, Molecular
DNA, Complementary
Humans
Liver - enzymology
Molecular Sequence Data
Sequence Homology, Amino Acid
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Summary:It is likely that endogenous inhibitors of the apical caspases such as caspase-9 exist to prevent undesirable activation of caspase cascades. A naturally occurring variant of caspase-9 named caspase-9S was cloned from human liver. Caspase-9S is missing most of the large subunit of caspase-9, including the catalytic site, but has the intact prodomain and small subunit. Caspase-9S did not show apoptotic activity in transfection analysis. Overexpression of caspase-9S inhibited apoptosis induced by caspase-9, indicating that caspase-9S is an endogenous dominant-negative of caspase-9. Moreover, caspase-9S inhibited apoptosis induced by tumor necrosis factor(TNF)-α, TNF factor-related apoptosis-inducing ligand (TRAIL), Bax, or Fas-associated death domain-containing protein (FADD) as well as the combination of Apaf-1 and caspase-9. In vitrobinding assays demonstrated that caspase-9S binds to Apaf-1 and blocks the binding of caspase-9 to Apaf-1. Coexpression of caspase-9 and caspase-9S mRNA was identified in various cell lines. Thus, caspase-9S acts as a dominant-negative inhibitor of caspase-9 activation, at least in part, by blocking Apaf-1-caspase-9 interaction.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.274.4.2072