XIAP acts as a switch between type I and type II FAS-induced apoptosis signalling

摘要

FAS (APO-1/CD95) and its physiological ligand, FASL, regulate apoptotic death of unwanted or dangerous cells in many tissues, 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 β-cells, amplification of the caspase cascade through caspase-8 mediated activation of the pro-apoptotic BCL-2 family member BID is essential^-. Here we show, that loss of X-chromosome linked inhibitor of apoptosis (XIAP)^, 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 rendered hepatocytes independent of BID for FAS-induced apoptosis signalling. These results show that XIAP is the critical discriminator between type I versus type II apoptosis signalling and suggest that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions.