Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins

Autor: Ana J. García-Sáez, Gregg G. Gundersen, Aida Peña-Blanco, Dan Grozki, Reuven Stein, Ayelet R. Amsalem-Zafran, Howard J. Worman, Liora Lindenboim, Didier Hodzic, Christoph Borner
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Cell Death Discovery, Vol 6, Iss 1, Pp 1-15 (2020)
Cell Death Discovery
ISSN: 2058-7716
Popis: 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.
Databáze: OpenAIRE
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