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

• Published in: The Journal of biological chemistry Vol. 274; no. 4; pp. 2072 - 2076
• Main Authors: Seol, Dai-Wu, Billiar, Timothy R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.01.1999; American Society for Biochemistry and Molecular Biology
• 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
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.4.2072

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.