NBK/BIK antagonizes MCL-1 and BCL-XL and activates BAK-mediated apoptosis in response to protein synthesis inhibition
NBK/BIK antagonizes MCL-1 and BCL-XL and activates BAK-mediated apoptosis in response to protein synthesis inhibition
复制标题
NBK/BIK 拮抗 MCL-1 和 BCL-XL，并响应蛋白质合成抑制激活 BAK 介导的细胞凋亡
DOI：
10.1101/gad.1522007
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发表时间：
2007-04-15
影响因子：
10.5
通讯作者：
Inouye, Masayori
中科院分区：
文献类型：
--
作者：
Shimazu, Tsutomu;Degenhardt, Kurt;Inouye, Masayori
核糖核酸酶、抗生素、细菌毒素和病毒抑制蛋白质合成，导致哺乳动物细胞凋亡。 BCL-2 蛋白家族如何响应蛋白合成的停止而调节细胞凋亡尚不清楚。在这里，我们证明了大肠杆菌毒素 MazF 通过裂解细胞 mRNA 抑制蛋白质合成并诱导哺乳动物细胞凋亡。 MazF 诱导的细胞凋亡需要促凋亡 BAK 及其上游调节因子（促凋亡 BH3 蛋白 NBK/BIK），但不需要 BIM、PUMA 或 NOXA。有趣的是，响应 MazF 诱导，NBK/BIK 通过将 BAK 从隔离 BAK 的抗凋亡蛋白 MCL-1 和 BCL-X-L 中取代来激活 BAK。此外，NBK/BIK或BAK缺陷的细胞对翻译的药理抑制和病毒介导的蛋白质合成关闭诱导的细胞死亡具有抵抗力。因此，仅 BH3 蛋白 NBK/BIK 是 BAK 依赖性细胞凋亡途径的顶端调节因子，响应于蛋白质合成的关闭，其功能是通过 MCL1 和 BCL-X-L 取代 BAK 的隔离。尽管 NBK/BIK 对于发育来说是可有可无的，但它是 BH3 唯一的目标蛋白，可被病毒灭活，这表明它通过细胞凋亡激活在病原体/毒素反应中发挥作用。
Ribonucleases, antibiotics, bacterial toxins, and viruses inhibit protein synthesis, which results in apoptosis in mammalian cells. How the BCL-2 family of proteins regulates apoptosis in response to the shutoff of protein synthesis is not known. Here we demonstrate that an Escherichia coli toxin, MazF, inhibited protein synthesis by cleavage of cellular mRNA and induced apoptosis in mammalian cells. MazF-induced apoptosis required proapoptotic BAK and its upstream regulator, the proapoptotic BH3-only protein NBK/BIK, but not BIM, PUMA, or NOXA. Interestingly, in response to MazF induction, NBK/BIK activated BAK by displacing it from anti-apoptotic proteins MCL-1 and BCL-X-L that sequester BAK. Furthermore, NBK/BIK- or BAK-deficient cells were resistant to cell death induced by pharmacologic inhibition of translation and by virus-mediated shutoff of protein synthesis. Thus, the BH3-only protein NBK/BIK is the apical regulator of a BAK-dependent apoptotic pathway in response to shutoff of protein synthesis that functions to displace BAK from sequestration by MCL1 and BCL-X-L. Although NBK/BIK is dispensable for development, it is the BH3- only protein targeted for inactivation by viruses, suggesting that it plays a role in pathogen/toxin response through apoptosis activation.