LINC complex protein nesprin-2 has pro-apoptotic activity via Bcl-2 family proteins.
LINC complex protein nesprin-2 has pro-apoptotic activity via Bcl-2 family proteins.
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LINC 复合蛋白 nesprin-2 通过 Bcl-2 家族蛋白具有促凋亡活性。
DOI：
10.1038/s41420-023-01763-w
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发表时间：
2024-01-15
影响因子：
7
通讯作者：
Stein, Reuven
中科院分区：
文献类型：
--
作者：
Lindenboim, Liora;Zohar, Hila;Gundersen, Gregg G.;Worman, Howard J.;Stein, Reuven
细胞凋亡内在途径由Bcl-2家族的效应子促细胞凋亡蛋白Bax和巴克对线粒体外膜的穿孔启动。Bax和巴克需要被激活，这是一个由Bcl-2家族的仅BH 3促凋亡成员的作用促进的过程。后者直接激活效应蛋白或拮抗促存活Bcl-2家族成员如Bcl-xL的作用。核被膜是凋亡机制的已知靶点;然而，它也可以充当凋亡的介体。我们以前表明，核膜蛋白nesprin-2，核骨架和细胞骨架（LINC）复合物的连接器的一个组成部分，可以结合到Bax的线粒体附近，并在凋亡细胞中的结合增加。我们现在表明，耗尽nesprin-2抑制凋亡线粒体途径，如Bax和巴克激活和细胞色素c释放所测量的。这种存活效应是Bcl-xL依赖性的。Nesprin-2耗竭还抑制缺乏Bcl-xL的细胞中巴克的N-末端的自发暴露，并增加线粒体中Bcl-xL和Bax的存在。这些结果表明，nesprin-2促进巴克激活和调节Bcl-2家族蛋白的线粒体易位/逆转录易位。我们的研究结果表明，一个新的凋亡途径，即核被膜，通过nesprin-2，调节细胞凋亡。
The apoptotic intrinsic pathway is initiated by perforation of the mitochondrial outer membrane by the effector pro-apoptotic proteins of the Bcl-2 family, Bax and Bak. Bax and Bak need to be activated, a process facilitated by the action of BH3-only pro-apoptotic members of the Bcl-2 family. The latter either directly activates the effector proteins or antagonizes the action of pro-survival Bcl-2 family members such as Bcl-xL. The nuclear envelope is a known target of the apoptotic machinery; however, it may also act as mediator of apoptosis. We showed previously that the nuclear envelope protein nesprin-2, a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex, can bind to Bax in close proximity to the mitochondria and that the binding increases in apoptotic cells. We now show that depleting nesprin-2 inhibits the apoptotic mitochondrial pathway as measured by Bax and Bak activation and cytochrome c release. This survival effect was Bcl-xL-dependent. Nesprin-2 depletion also inhibited spontaneous exposure of the N-terminus of Bak in cells lacking Bcl-xL and increased the presence of Bcl-xL and Bax in the mitochondria. These results indicate that nesprin-2 promotes Bak activation and regulates mitochondrial translocation/retrotranslocation of Bcl-2 family proteins. Our findings demonstrate a new apoptotic pathway whereby the nuclear envelope, via nesprin-2, regulates apoptosis.
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