Mcl-1 and Bcl-xL sequestration of Bak confers differential resistance to BH3-only proteins

The prosurvival Bcl-2 family proteins Mcl-1 and Bcl-x(L) inhibit apoptosis by sequestering BH3-only proteins such as Bid and Bim (MODE 1) or the effector proteins Bak and Bax (MODE 2). To better understand the contributions of MODE 1 and MODE 2 in blocking cell death, and thus how to bypass resistance to cell death, we examined prescribed mixtures of Bcl-2 family proteins. In a Bim and Bak mixture, Bcl-x(L) and Mcl-1 each sequestered not only Bim but also Bak as it became activated by Bim. In contrast, in a Bid and Bak mixture, Bcl-x(L) preferentially sequestered Bid while Mcl-1 preferentially sequestered Bak. Notably, Bcl-x(L) could sequester Bak in response to the BH3 mimetic ABT-737, despite this molecule targeting Bcl-x(L). These findings highlight the importance of Bak sequestration in resistance to anti-cancer treatments, including BH3 mimetics.