XIAP Discriminates Between Type I and Type II FAS-induced Apoptosis

Nature. 2009 Aug 20;460(7258):1035-9. doi: 10.1038/nature08229. Epub 2009 Jul 22.

Abstract

FAS (also called APO-1 and CD95) and its physiological ligand, FASL, regulate apoptosis of unwanted or dangerous cells, functioning as a guardian against autoimmunity and cancer development. Distinct cell types differ in the mechanisms by which the 'death receptor' FAS triggers their apoptosis. In type I cells, such as lymphocytes, activation of 'effector caspases' by FAS-induced activation of caspase-8 suffices for cell killing, whereas in type II cells, including hepatocytes and pancreatic beta-cells, caspase cascade amplification through caspase-8-mediated activation of the pro-apoptotic BCL-2 family member BID (BH3 interacting domain death agonist) is essential. Here we show that loss of XIAP (X-chromosome linked inhibitor of apoptosis protein) function by gene targeting or treatment with a second mitochondria-derived activator of caspases (SMAC, also called DIABLO; direct IAP-binding protein with low pI) mimetic drug in mice rendered hepatocytes and beta-cells independent of BID for FAS-induced apoptosis. These results show that XIAP is the critical discriminator between type I and type II apoptosis signalling and suggest that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • BH3 Interacting Domain Death Agonist Protein / deficiency
  • BH3 Interacting Domain Death Agonist Protein / genetics
  • Biomimetic Materials / pharmacology
  • Caspase Inhibitors
  • Enzyme Activation
  • Fas Ligand Protein / metabolism
  • Female
  • Hepatitis / metabolism
  • Hepatitis / pathology
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Signal Transduction
  • Thymus Gland / cytology
  • Thymus Gland / drug effects
  • X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors
  • X-Linked Inhibitor of Apoptosis Protein / deficiency
  • X-Linked Inhibitor of Apoptosis Protein / genetics
  • X-Linked Inhibitor of Apoptosis Protein / metabolism*
  • fas Receptor / antagonists & inhibitors
  • fas Receptor / immunology
  • fas Receptor / metabolism*

Substances

  • BH3 Interacting Domain Death Agonist Protein
  • Bid protein, mouse
  • Caspase Inhibitors
  • Fas Ligand Protein
  • Fasl protein, mouse
  • X-Linked Inhibitor of Apoptosis Protein
  • fas Receptor