BCL-2-family protein tBID can act as a BAX-like effector of apoptosis

During apoptosis, the BCL-2-family protein tBID promotes mitochondrial permeabilization by activating BAX and BAK and by blocking anti-apoptotic BCL-2 members. Here, we report that tBID can also mediate mitochondrial permeabilization by itself, resulting in release of cytochrome c and mitochondrial DNA, caspase activation, and apoptosis even in absence of BAX and BAK. This previously unrecognized activity of tBID depends on helix 6, homologous to the pore-forming regions of BAX and BAK, and can be blocked by pro-survival BCL-2 proteins. Importantly, tBID-mediated mitochondrial permeabilization independent of BAX and BAK is physiologically relevant for SMAC release in the immune response against Shigella infection. Furthermore, it can be exploited to kill leukaemia cells with acquired venetoclax resistance due to lack of active BAX and BAK. Our findings define tBID as an effector of mitochondrial permeabilization in apoptosis and provide a new paradigm for BCL-2 proteins, with implications for anti-bacterial immunity and cancer therapy.

在细胞凋亡过程中，BCL-2家族蛋白tBID可通过激活BAX与BAK，并拮抗抗凋亡BCL-2家族成员，从而促进线粒体通透化。本研究发现，tBID亦可独立介导线粒体通透化：即使在BAX与BAK缺失的情况下，仍可诱导细胞色素c与线粒体DNA释放、激活半胱天冬酶（caspase），并最终引发细胞凋亡。tBID的这一此前未被识别的活性依赖于其第6螺旋结构域——该结构域与BAX、BAK的孔形成区域同源——且可被促存活BCL-2家族蛋白所阻断。值得注意的是，不依赖BAX与BAK的tBID介导的线粒体通透化，在抗志贺氏菌（Shigella）感染的免疫应答中，对于SMAC的释放具有生理相关性。此外，该活性可被用于靶向杀灭因功能性BAX与BAK缺失而获得维奈克拉（venetoclax）耐药性的白血病细胞。本研究将tBID确立为细胞凋亡过程中线粒体通透化的效应分子，并为BCL-2家族蛋白的功能机制提供了全新范式，其研究结果对抗菌免疫与肿瘤治疗领域均具有重要启示意义。