Universität zu Köln

Lindenboim, Liora, Grozki, Dan, Amsalem-Zafran, Ayelet R., Pena-Blanco, Aida, Gundersen, Gregg G., Borner, Christoph, Hodzic, Didier, Garcia-Saez, Ana J., Worman, Howard J. and Stein, Reuven (2020). Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins. Cell Death Discov., 6 (1). LONDON: SPRINGERNATURE. ISSN 2058-7716

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Abstract

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 alpha 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lindenboim, Liora UNSPECIFIED UNSPECIFIED UNSPECIFIED Grozki, Dan UNSPECIFIED UNSPECIFIED UNSPECIFIED Amsalem-Zafran, Ayelet R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pena-Blanco, Aida UNSPECIFIED UNSPECIFIED UNSPECIFIED Gundersen, Gregg G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Borner, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Hodzic, Didier UNSPECIFIED UNSPECIFIED UNSPECIFIED Garcia-Saez, Ana J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Worman, Howard J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stein, Reuven UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-318848
DOI:	10.1038/s41420-020-00327-6
Journal or Publication Title:	Cell Death Discov.
Volume:	6
Number:	1
Date:	2020
Publisher:	SPRINGERNATURE
Place of Publication:	LONDON
ISSN:	2058-7716
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NUCLEAR-ENVELOPE PROTEINS; DNA-DAMAGE; MEMBRANE; RUPTURE; ACTIN; FAMILY; LAMIN; DISRUPTIONS; DEFORMATION; EXPRESSION Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/31884