XIAP discriminates between type I and type II FAS-induced apoptosis.
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.
Jost
Philipp J
PJ
The Walter and Eliza Hall Institute of Medical Research, Melbourne University, Parkville, Victoria 3050, Australia.
Grabow
Stephanie
S
Gray
Daniel
D
McKenzie
Mark D
MD
Nachbur
Ueli
U
Huang
David C S
DC
Bouillet
Philippe
P
Thomas
Helen E
HE
Borner
Christoph
C
Silke
John
J
Strasser
Andreas
A
Kaufmann
Thomas
T
D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000172:deficiency / Q000235:genetics; D040761:Biomimetic Materials / Q000494:pharmacology; D061945:Caspase Inhibitors; D004789:Enzyme Activation; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D006505:Hepatitis / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D061945:Caspase Inhibitors; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D051636:X-Linked Inhibitor of Apoptosis Protein; D019014:fas Receptor