Apoptosis is triggered when prosurvival Bcl-2 proteins cannot restrain Bax

作者：Fletchera Jamie I; Meu**urger Sarina; Hawkins Christine J; Riglar David T; Lee Erinna F; Fairlie W Douglas; Huang David C S^*; Adams Jerry M

来源：Proceedings of the National Academy of Sciences, 2008, 105(47): 18081-18087.

DOI：10.1073/pnas.0808691105

• BH3 domain
• control of apoptosis
• mitochondria
• protein association
• membrane association

A central issue in the control of apoptosis is whether its essential mediators Bax and Bak must be restrained by Bcl-2-like prosurvival relatives to prevent their damaging mitochondria and unleashing apoptosis. The issue is particularly vexed for Bax, which is largely a cytosolic monomer in unstressed cells. To determine whether Bax regulation requires its binding by prosurvival relatives, we replaced a conserved aspartate in its BH3 interaction domain with arginine. Bax D68R functioned and behaved like wild-type Bax in localization and activation but had greatly impaired binding to the prosurvival family members. Nevertheless, Bcl-x(L) remained able to block apoptosis induced by Bax D68R. Whereas cells with sufficient Bcl-x(L) tolerated expression of Bax D68R, it provoked apoptosis when Bcl-x(L) was absent, downregulated, or inactivated. Moreover, Bax D68R rendered membrane bound by a C-terminal anchor mutation overwhelmed endogenous Bcl-x(L) and killed cells. These unexpected results suggest that engagement of Bax by its prosurvival relatives is a major barrier to its full activation. We propose that the Bcl-2-like proteins must capture the small proportion of Bax molecules with an exposed BH3 domain, probably on the mitochondrial membrane, to prevent Bax-imposed cell death, but that Bcl-x(L) also controls Bax by other mechanisms.

• 出版日期2008-11-25
• 单位河北医科大学