VDAC2 inhibits BAK activation and mitochondrial apoptosis
VDAC2 inhibits BAK activation and mitochondrial apoptosis
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DOI：
10.1126/science.1083995
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发表时间：
2003-07-25
期刊：
影响因子：
56.9
通讯作者：
Korsmeyer, SJ
中科院分区：
文献类型：
--
作者：
Cheng, EHY;Sheiko, TV;Korsmeyer, SJ
启动线粒体凋亡途径需要多域促凋亡分子 BAK 或 BAX。细胞如何将潜在致命的促凋亡效应子 BAK 维持在线粒体的单体非活性构象中尚不清楚。在活细胞中，我们发现 BAK 与线粒体外膜蛋白 VDAC2 复合，VDAC2 是一种低丰度的 VDAC 亚型，与 BAK 的非活性构象异构体特异性相互作用。缺乏VDAC2的细胞，但缺乏更丰富的VDAC1的细胞，表现出增强的BAK寡聚化，并且更容易发生细胞凋亡。相反，VDAC2 的过度表达选择性地阻止 BAK 激活并抑制线粒体凋亡途径。死亡信号激活“仅 BH3”分子，例如 tBID、BIM 或 BAD，这些分子取代 BAK 中的 VDAC2，从而实现 BAK 的同源寡聚化和细胞凋亡。因此，VDAC2（一种仅限于哺乳动物的亚型）调节 BAK 的活性，并在线粒体生理学和核心细胞凋亡途径之间提供联系。
The multidomain proapoptotic molecules BAK or BAX are required to initiate the mitochondrial pathway of apoptosis. How cells maintain the potentially lethal proapoptotic effector BAK in a monomeric inactive conformation at mitochondria is unknown. In viable cells, we found BAK complexed with mitochondrial outer-membrane protein VDAC2, a VDAC isoform present in low abundance that interacts specifically with the inactive conformer of BAK. Cells deficient in VDAC2, but not cells lacking the more abundant VDAC1, exhibited enhanced BAK oligomerization and were more susceptible to apoptotic death. Conversely, overexpression of VDAC2 selectively prevented BAK activation and inhibited the mitochondrial apoptotic pathway. Death signals activate "BH3-only" molecules such as tBID, BIM, or BAD, which displace VDAC2 from BAK, enabling homo-oligomerization of BAK and apoptosis. Thus, VDAC2, an isoform restricted to mammals, regulates the activity of BAK and provides a connection between mitochondrial physiology and the core apoptotic pathway.