Proapoptotic BH3-Only Proteins Have Different Activation Preferences

Many chemotherapeutic agents activate the mitochondrial apoptotic pathway, which is regulated by proapoptotic BCL-2 protein family members such as BID and BIM. BID and BIM activate BAK and BAX, which then oligomerize and commit the cell to death by directly inducing mitochondrial outer membrane permeabilization (MOMP). Although BID and BIM have differential expression patterns and can be induced by distinct apoptotic stimuli, it has been assumed that BID and BIM are functionally redundant activators of BAK and BAX. Using a fluorescence-based assay to detect mitochondrial transmembrane potential, Sarosiek and colleagues showed that the mitochondrial response to a BID peptide was attenuated in Bak^−/−, but not Bax^−/− murine embryonic fibroblasts (MEF), whereas the response to a BIM peptide was reduced only in Bax^−/− MEFs. Moreover, in MEFs lacking BID and BIM, a lower concentration of exogenous BID than BIM was needed to induce BAK oligomerization, whereas the opposite was true for BAX oligomerization. These findings suggest that, although BID and BIM are each capable of activating BAK and BAX, BID preferentially activates BAK and BIM preferentially activates BAX, a trend which was observed in multiple cell types. Intriguingly, Bak^−/− MEFs were also less sensitive to drugs such as topoisomerase inhibitors that induce MOMP in a BID-dependent manner, raising the possibility that BAK deficiency in tumors may confer resistance to these agents. An analysis of patients with high-grade serous ovarian adenocarcinomas revealed that 23.2% of patients treated with topoisomerase inhibitors had heterozygous or homozygous loss of BAK1, and that loss of one or both alleles was significantly associated with shorter overall survival. Although the mechanisms underlying BAK and BAX activation preferences remain to be identified, these results suggest that the BAK and BID status of patients should be considered prior to treatment with certain chemotherapeutic agents.

Sarosiek KA, Chi X, Bachman JA, Sims JJ, Montero J, Pavel L, et al. BID preferentially activates BAK while BIM preferentially activates BAX, affecting chemotherapy response. Mol Cell 2013;51:751–65.

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