The BCL-2 Protein BAK Is Required for Long-chain Ceramide Generation during Apoptosis

摘要: The BCL-2 family members BAK and BAX are required for apoptosis trigger mitochondrial outer membrane permeabilization (MOMP). Here we identify a MOMP-independent function of as factor long-chain ceramide production in response to pro-apoptotic stress. UV-C irradiation wild-type (WT) cells increased ceramides; blocking generation prevented caspase activation cell death, demonstrating that ceramides play key role UV-C-induced apoptosis. In contrast, did not increase double knock-out cells. Notably, this was specific the type (baby mouse kidney cells, hematopoietic) nor apoptotic stimulus employed (UV-C, cisplatin, growth withdrawal). Importantly, dependent on presence BAK, but BAX. However, independent known downstream actions (MOMP or activation), suggesting novel Finally, enzymatic assays identified synthase mechanism by which regulates metabolism. There no change CerS expression at message protein level, indicating regulation post-translational level. Moreover, activity KO microsomes can be reactivated upon addition BAK-containing microsomes. data presented indicate ceramide-induced is during By establishing unique metabolism, these studies further demonstrate seemingly redundant proteins have distinct mechanisms action induction.