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, 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)-alpha, 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 vitro binding 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.
Seol
D W
DW
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. seold+@pitt.edu
Billiar
T R
TR
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D020134:Catalytic Domain; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary; D006801:Humans; D008099:Liver / Q000201:enzymology; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid
D018076:DNA, Complementary; C513669:caspase 9s, human; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases