Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins.
Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins.
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DOI：
10.1038/s41420-020-00327-6
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发表时间：
2020
影响因子：
7
通讯作者：
Stein R
中科院分区：
文献类型：
--
作者：
Lindenboim L;Grozki D;Amsalem-Zafran AR;Peña-Blanco A;Gundersen GG;Borner C;Hodzic D;Garcia-Sáez AJ;Worman HJ;Stein R
Bcl-2家族蛋白的典型功能是调节线粒体膜完整性。响应于凋亡信号，多结构域促凋亡蛋白Bax和巴克被激活，并通过一种机制使线粒体外膜活化，该机制被它们与家族的促存活成员的相互作用抑制。然而，其他研究表明，Bax和巴克可能有额外的，非典型的功能，其中包括应激诱导的核膜破裂和核蛋白排放到胞质溶胶。我们在这里表明，凋亡刺激顺铂和星形孢菌素诱导Bax/Bak-dependent降解和亚细胞再分布nesprin-1和nesprin-2，但不是nesprin-3，连接器的核骨架和细胞骨架（LINC）复合物。这种降解和再分布不依赖于半胱氨酸蛋白酶，并且在Bax/巴克双敲除（DKO）小鼠胚胎成纤维细胞（MEF）中不发生。Bax/巴克DKO MEFs中Bax的再表达通过需要Bax膜定位和α螺旋5/6的完整性以及Bcl-2同源3（BH 3）结构域的机制恢复了应激诱导的nesprin-2的再分布。我们发现，nesprin-2相互作用与Bax在小鼠和人类细胞的核周线粒体附近。这种相互作用需要Bax的线粒体靶向和N端区域，而不是BH 3结构域。我们的研究结果确定nesprin-2作为Bax的结合伙伴，也是Bax在损害LINC复合物的完整性的新功能。
The canonical function of Bcl-2 family proteins is to regulate mitochondrial membrane integrity. In response to apoptotic signals the multi-domain pro-apoptotic proteins Bax and Bak are activated and perforate the mitochondrial outer membrane by a mechanism which is inhibited by their interaction with pro-survival members of the family. However, other studies have shown that Bax and Bak may have additional, non-canonical functions, which include stress-induced nuclear envelope rupture and discharge of nuclear proteins into the cytosol. We show here that the apoptotic stimuli cisplatin and staurosporine induce a Bax/Bak-dependent degradation and subcellular redistribution of nesprin-1 and nesprin-2 but not nesprin-3, of the linker of nucleoskeleton and cytoskeleton (LINC) complex. The degradation and redistribution were caspase-independent and did not occur in Bax/Bak double knockout (DKO) mouse embryo fibroblasts (MEFs). Re-expression of Bax in Bax/Bak DKO MEFs restored stress-induced redistribution of nesprin-2 by a mechanism which requires Bax membrane localization and integrity of the α helices 5/6, and the Bcl-2 homology 3 (BH3) domain. We found that nesprin-2 interacts with Bax in close proximity to perinuclear mitochondria in mouse and human cells. This interaction requires the mitochondrial targeting and N-terminal region but not the BH3 domain of Bax. Our results identify nesprin-2 as a Bax binding partner and also a new function of Bax in impairing the integrity of the LINC complex.