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- Title
Ectopic expression of the serine protease inhibitor PI9 modulates death receptor-mediated apoptosis.
- Authors
Kummer, J A; Micheau, O; Schneider, P; Bovenschen, N; Broekhuizen, R; Quadir, R; Strik, M C M; Hack, C E; Tschopp, J
- 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
Cell death and differentiation, 2007, Vol 14, Issue 8, p1486
- ISSN
1350-9047
- Publication type
Journal Article
- DOI
10.1038/sj.cdd.4402152