Nesprin-2, a component of the LINC complex, is needed for apoptotic cell death

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, our previous studies have shown that Bax and Bak have, in addition to mitochondrial apoptotic function, non-canonical functions, which include stress-induced nuclear envelope rupture and discharge of nuclear proteins into the cytosol. We showed that apoptotic stimuli induce a Bax/Bak-dependent and caspase-independent degradation and subcellular redistribution of the linker of nucleoskeleton and cytoskeleton (LINC) complex proteins nesprin-1 and nesprin-2. We also found that nesprin-2 interacts with Bax in close proximity to perinuclear mitochondria in mouse and human cells. In this study we investigate the potential involvement of nesprin-2 in apoptotic cell death. We found that downregulating nesprin-2 protein levels in wild-type mouse embryonic fibroblasts (MEFs) by siRNA or by shRNA reduced cell death, cytochrome c release and Bax and Bak activation but not nuclear proteins redistribution. This survival effect was inhibited in Bcl-xL knockout MEFs or in the presence of Bcl-xL siRNA. These findings suggest that nesprin-2 has a pro-apoptotic effect that is mediated via Bcl-xL.