BH3 domains of BH3-only proteins differentially regulate bax-mediated mitochondrial membrane permeabilization both directly and indirectly
BH3 domains of BH3-only proteins differentially regulate bax-mediated mitochondrial membrane permeabilization both directly and indirectly
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DOI：
10.1016/j.molcel.2005.02.003
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发表时间：
2005-02-18
期刊：
影响因子：
16
通讯作者：
Newmeyer, DD
中科院分区：
文献类型：
--
作者：
Kuwana, T;Bouchier-Hayes, L;Newmeyer, DD
利用Bax依赖的膜通透性分析，我们证明了与Bc l-2家族“BH3-only”蛋白的BH3结构域相对应的多肽具有双重功能。几个BH3多肽可以解除抗细胞凋亡的BclX-L和/或Mcl-1蛋白对Bax的抑制作用，有些BH3肽对BclX-L或Mcl-1具有特异性。除了具有这种去抑制功能外，Bid和Bim多肽还直接激活Bax，是唯一被测试的能够有效地诱导培养细胞线粒体释放细胞色素c的BH3多肽。此外，Bax激活剂分子(切割的BID蛋白和Bim BH3多肽)与去阻滞剂BH3多肽一起被引入细胞内，协同诱导细胞色素c的释放。这些观察结果支持BH3结构域功能的统一模型，包括对其他Bcl-2家族成员的正向和负向调控。在这个模型中，除非存在BAX或BAK的直接激活剂，否则简单的抑制抗凋亡功能不足以诱导细胞凋亡。
Using a Bax-dependent membrane-permeabilization assay, we show that peptides corresponding to the BH3 domains of Bcl-2 family "BH3-only" proteins have dual functions. Several BH3 peptides relieved the inhibition of Bax caused by the antiapoptotic Bcl-X-L and/or Mcl-1 proteins, some displaying a specificity for either Bcl-X-L or Mcl-1. Besides having this derepression function, the Bid and Bim peptides activated Bax directly and were the only BH3 peptides tested that could potently induce cytochrome c release from mitochondria in cultured cells. Furthermore, Bax activator molecules (cleaved Bid protein and the Bim BH3 peptide) synergistically induced cytochrome c release when introduced into cells along with derepressor BH3 peptides. These observations support a unified model of BH3 domain function, encompassing both positive and negative regulation of other Bcl-2 family members. In this model, the simple inhibition of antiapoptotic functions is insufficient to induce apoptosis unless a direct activator of Bax or Bak is present.