Apoptosis is triggered when prosurvival Bcl-2 proteins cannot restrain Bax
Apoptosis is triggered when prosurvival Bcl-2 proteins cannot restrain Bax
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DOI：
10.1073/pnas.0808691105
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发表时间：
2008-11-25
影响因子：
11.1
通讯作者：
Adams, Jerry M.
中科院分区：
文献类型：
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作者：
Fletchera, Jamie I.;Meusburger, Sarina;Adams, Jerry M.
细胞凋亡调控的一个核心问题是其必需的介质Bax和Bak是否必须受到bcl -2样促存活亲缘体的抑制，以防止它们破坏线粒体并释放细胞凋亡。对于Bax来说，这个问题尤其令人烦恼，它主要是一种非应激细胞中的细胞质单体。为了确定Bax调节是否需要其与促存活亲缘蛋白结合，我们用精氨酸取代了BH3相互作用域中保守的天冬氨酸。Bax D68R在定位和激活方面的功能和行为与野生型Bax相似，但与促生存家族成员的结合受到严重损害。然而，Bcl-x(L)仍然能够阻断Bax D68R诱导的细胞凋亡。然而，具有足够Bcl-x(L)的细胞耐受Bax D68R的表达，当Bcl-x(L)缺失、下调或失活时，它会引发细胞凋亡。此外，Bax D68R使c末端锚定突变结合的膜淹没内源性Bcl-x(L)并杀死细胞。这些意想不到的结果表明，Bax的亲存活亲缘关系是其完全激活的主要障碍。我们提出bcl -2样蛋白必须捕获一小部分暴露BH3结构域的Bax分子，可能在线粒体膜上，以防止Bax引起的细胞死亡，但Bcl-x(L)也通过其他机制控制Bax。
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.