Ectopic expression of the serine protease inhibitor PI9 modulates death receptor-mediated apoptosis

Cell Death Differ. 2007 Aug;14(8):1486-96. doi: 10.1038/sj.cdd.4402152. Epub 2007 May 4.

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