Journal Article

XIAP discriminates between type I and type II FAS-induced apoptosis

Strasser, Andreas, Gray, Daniel, Kaufmann, Thomas, Jost, Philipp J., Bouillet, Philippe, Huang, David C. S., Borner, Christoph, McKenzie, Mark D., Grabow, Stephanie, Nachbur, Ueli, Thomas, Helen E., Silke, John

2009

Overview

Divergent routes to cell death One of the current problems in cell death research is to understand why distinct cell types (type I versus type II cells) differ so markedly in the mechanisms by which the 'death receptor' FAS triggers their apoptosis. Type I cells die by FAS-induced activation of caspase-8 and downstream effector caspases, leading a quick demise; type II cells, however, have to amplify the caspase cascade through caspase-8-mediated activation of the 'death agonist' BID, and subsequent activation of caspase-9. Jost et al . now show that the inhibitor of apoptosis, XIAP, makes all the difference for these cells: without XIAP a type II cell dies just like any cell type I. The authors suggest that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions since they might unintentionally sensitize non-target cells to die. The 'death receptor' FAS regulates apoptosis of unwanted or dangerous cells, functioning as a guardian against autoimmunity and cancer development. Distinct cell types differ in the mechanisms by which FAS triggers apoptosis: in type I cells, FAS-induced activation of caspase-8 suffices for cell killing, whereas in type II cells there must be caspase cascade amplification. Here it is shown that the inhibitor of apoptosis XIAP is the critical factor determining this — without it, a type II cell dies in the same way as a type I cell. 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 1 , 2 , 3 , 4 . Distinct cell types differ in the mechanisms by which the ‘death receptor’ FAS triggers their apoptosis 1 , 2 , 3 , 4 . 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 β-cells, caspase cascade amplification through caspase-8-mediated activation of the pro-apoptotic BCL-2 family member BID (BH3 interacting domain death agonist) 5 is essential 6 , 7 , 8 . Here we show that loss of XIAP (X-chromosome linked inhibitor of apoptosis protein) 9 , 10 function by gene targeting or treatment with a second mitochondria-derived activator of caspases (SMAC 11 , also called DIABLO 12 ; direct IAP-binding protein with low pI) mimetic drug in mice rendered hepatocytes and β-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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Ageing, cell death / Animals / Apoptosis / BH3 Interacting Domain Death Agonist Protein - deficiency / BH3 Interacting Domain Death Agonist Protein - genetics / Biological and medical sciences / Biomimetic Materials - pharmacology / Cancer / Cancer therapies / Caspase Inhibitors / Cell physiology / Cells / Cellular proteins / Cellular signal transduction / Drug therapy / Enzyme Activation / Enzyme inhibitors / Fas Ligand Protein - metabolism / fas Receptor - antagonists & inhibitors / fas Receptor - immunology / fas Receptor - metabolism / Female / Fundamental and applied biological sciences. Psychology / Health aspects / Hepatitis / Hepatitis - metabolism / Hepatitis - pathology / Hepatocytes - cytology / Hepatocytes - drug effects / Hepatocytes - metabolism / Humanities and Social Sciences / letter / Lymphocytes / Male / Mice / Mice, Inbred C57BL / Molecular and cellular biology / multidisciplinary / Physiological aspects / Rodents / Science / Science (multidisciplinary) / Signal Transduction / Substrates / 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