BCL-2-family protein tBID can act as a BAX-like effector of apoptosis.
BCL-2-family protein tBID can act as a BAX-like effector of apoptosis.
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DOI：
10.15252/embj.2021108690
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发表时间：
2022-12-17
期刊：
影响因子：
--
通讯作者：
Garcia-Saez AJ
中科院分区：
文献类型：
--
作者：
Flores-Romero H;Hohorst L;John M;Albert MC;King LE;Beckmann L;Szabo T;Hertlein V;Luo X;Villunger A;Frenzel LP;Kashkar H;Garcia-Saez AJ
在细胞凋亡过程中，BCL - 2家族蛋白tBID通过激活BAX和BAK以及阻断抗凋亡BCL - 2成员来促进线粒体通透性。在此，我们报道tBID本身也能介导线粒体通透性，即使在缺乏BAX和BAK的情况下，也能导致细胞色素c和线粒体DNA的释放、caspase的激活和凋亡。这种先前未被识别的tBID活性依赖于螺旋6，它与BAX和BAK的孔形成区域同源，并且可以被促生存的BCL - 2蛋白阻断。重要的是，tBID介导的线粒体通透性独立于BAX和BAK，与志贺菌感染免疫应答中的SMAC释放在生理上相关。此外，由于缺乏活性BAX和BAK，它可以被用来杀死具有获得性venetoclax抗性的白血病细胞。我们的研究结果将tBID定义为细胞凋亡中线粒体通透性的影响因子，并为BCL - 2蛋白提供了一个新的范式，对抗菌免疫和癌症治疗具有重要意义。促凋亡BCL - 2家族蛋白tBID不仅可以通过BAX/BAK激活促进线粒体通透性，还可以通过自身介导venetoclax耐药白血病细胞的抗菌反应和凋亡。
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. Pro‐apoptotic BCL‐2‐family protein tBID can promote mitochondrial permeabilization not just via BAX/BAK activation, but also on its own to mediate antibacterial responses and apoptosis of venetoclax‐resistant leukaemia cells.
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