Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins
Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins
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DOI：
10.1101/gad.1304105
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发表时间：
2005-06-01
影响因子：
10.5
通讯作者：
Huang, DCS
中科院分区：
文献类型：
--
作者：
Willis, SN;Chen, L;Huang, DCS
细胞凋亡在很大程度上是由Bcl-2蛋白家族成员之间的相互作用决定的。它的三个亚家族有不同的作用：BH3-only蛋白通过BH3结构域与促存活相关蛋白结合来触发细胞凋亡，而促凋亡的Bax和Bak具有重要的下游作用，包括细胞器膜的通透性和诱导半胱天冬酶激活。我们研究了Bak的调控，发现在健康细胞中，Bak与Mcl-1和Bcl-x(L)相关，但令人惊讶的是，与Bcl-2、Bcl-w或A1无关。这些相互作用需要Bak BH3结构域，这也是Bak二聚化和杀伤活性所必需的。当细胞毒性信号激活bh3蛋白时，bh3蛋白可以结合Mcl-1和Bcl-x(L)（如Noxa + Bad）， Bak移位并诱导细胞死亡。因此，BH3-only蛋白Noxa可以与Mcl-1结合，取代Bak，促进Mcl-1降解，但Bak介导的细胞死亡也需要Bcl-x被其他BH3-only蛋白中和。结果表明，Bak仅受Mcl-1和Bcl-x的控制，只有在两者均不受抑制的情况下才能诱导细胞凋亡。不同的促生存蛋白具有选择性作用，这一发现对于设计针对Bcl-2家族的抗癌药物具有重要意义。
Commitment of cells to apoptosis is governed largely by the interaction between members of the Bcl-2 protein family. its three subfamilies have distinct roles: The BH3-only proteins trigger apoptosis by binding via their BH3 domain to prosurvival relatives, while the proapoptotic Bax and Bak have an essential downstream role involving permeabilization of organellar membranes and induction of caspase activation. We have investigated the regulation of Bak and find that, in healthy cells, Bak associates with Mcl-1 and Bcl-x(L) but surprisingly not Bcl-2, Bcl-w, or A1. These interactions require the Bak BH3 domain, which is also necessary for Bak dimerization and killing activity. When cytotoxic signals activate BH3-only proteins that can engage both Mcl-1 and Bcl-x(L) (such as Noxa plus Bad), Bak is displaced and induces cell death. Accordingly, the BH3-only protein Noxa could bind to Mcl-1, displace Bak, and promote Mcl-1 degradation, but Bak-mediated cell death also required neutralization of Bcl-x, by other BH3-only proteins. The results indicate that Bak is held in check solely by Mcl-1 and Bcl-x, and induces apoptosis only if freed from both. The finding that different prosurvival proteins have selective roles has notable implications for the design of anti-cancer drugs that target the Bcl-2 family.