The proteins BAX and BAK act as a key decision point, regulating apoptosis by controlling the permeability of the mitochondrial outer membrane. Evidence has been presented for two mechanisms of activation of BAX and BAK: an indirect mechanism where proapoptotic proteins neutralize the antiapoptotic effects of the protein BCL-2 and its relatives, and direct activation of BAX and BAK by BIM, BID, or PUMA. Analysis of the situation in vivo is complicated by the overlapping function of BIM, BID, and PUMA. Ren et al. (see the Perspective by Martin) thus analyzed triple-knockout mice lacking BIM, BID, and PUMA. Apoptosis during mouse development required a direct effect of one of these proteins to activate BAX or BAK, thereby promoting cell death.
D. Ren, H.-C. Tu, H. Kim, G. X. Wang, G. R. Bean, O. Takeuchi, J. R. Jeffers, G. P. Zambetti, J. J.-D. Hsieh, E. H.-Y. Cheng, BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science 330, 1390–1393 (2010). [Abstract] [Full Text]