Article: article from journal or magazin.
Ectopic expression of the serine protease inhibitor PI9 modulates death receptor-mediated apoptosis.
Cell Death and Differentiation
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.
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) 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
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