Abstract
Apoptosis is a highly controlled process, whose triggering is associated with the activation of caspases. Apoptosis can be induced via a subgroup of the tumor necrosis factor (TNF) receptor superfamily, which recruit and activate pro-caspase-8 and -10. Regulation of apoptosis is achieved by several inhibitors, including c-FLICE-inhibitory protein, which prevents apoptosis by inhibiting the pro-apoptotic activation of upstream caspases. Here we show that the human intracellular serine protease inhibitor (serpin), protease inhibitor 9 (PI9), inhibits TNF-, TNF-related apoptosis-inducing ligand- and Fas ligand-mediated apoptosis in certain TNF-sensitive cell lines. The reactive center P1 residue of PI9 was required for this inhibition since PI9 harboring a Glu --> Ala mutation in its reactive center failed to impair death receptor-induced cell death. This suggests a classical serpin-protease interaction. Indeed, PI9 inhibited apoptotic death by directly interacting with the intermediate active forms of caspase-8 and -10. This indicates that PI9 can regulate pro-apoptotic apical caspases.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Apoptosis / physiology*
-
Caspase 10 / metabolism
-
Caspase 3 / metabolism
-
Caspase 8 / metabolism
-
Cell Line, Tumor
-
Fas Ligand Protein / physiology
-
Humans
-
Ligands
-
Mice
-
Models, Biological
-
Poly (ADP-Ribose) Polymerase-1
-
Poly(ADP-ribose) Polymerases / metabolism
-
Protein Processing, Post-Translational
-
Receptors, Death Domain / physiology*
-
Recombinant Proteins / genetics
-
Recombinant Proteins / metabolism
-
Serine Proteinase Inhibitors / genetics*
-
Serine Proteinase Inhibitors / physiology*
-
Serpins / genetics*
-
Serpins / physiology*
-
Signal Transduction
-
TNF-Related Apoptosis-Inducing Ligand / physiology
-
Transduction, Genetic
-
Tumor Necrosis Factor-alpha / physiology
Substances
-
FASLG protein, human
-
Fas Ligand Protein
-
Ligands
-
Receptors, Death Domain
-
Recombinant Proteins
-
SERPINB9 protein, human
-
Serine Proteinase Inhibitors
-
Serpins
-
TNF-Related Apoptosis-Inducing Ligand
-
TNFSF10 protein, human
-
Tumor Necrosis Factor-alpha
-
PARP1 protein, human
-
Poly (ADP-Ribose) Polymerase-1
-
Poly(ADP-ribose) Polymerases
-
CASP3 protein, human
-
CASP8 protein, human
-
Caspase 10
-
Caspase 3
-
Caspase 8
-
CASP10 protein, human