TY - JOUR
T1 - Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins
AU - Lindenboim, Liora
AU - Grozki, Dan
AU - Amsalem-Zafran, Ayelet R.
AU - Peña-Blanco, Aida
AU - Gundersen, Gregg G.
AU - Borner, Christoph
AU - Hodzic, Didier
AU - Garcia-Sáez, Ana J.
AU - Worman, Howard J.
AU - Stein, Reuven
N1 - Funding Information:
We thank Richard Youle (National Institutes of Health, Bethesda, MD, USA) for providing the HCT116 DKO cells and Christian Bernes (Friedrich-Loeffler-Institut, Jena, Germany) for providing the pWHE644 and pWHE655 plasmids. This work was supported by the Recanati Foundation for Medical Research (to R.S), NIH grant RO1AR068636 to G.G.G. and H.J.W. and NIH grant R35GM136403 to G.G.G.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85091202061&partnerID=8YFLogxK
U2 - 10.1038/s41420-020-00327-6
DO - 10.1038/s41420-020-00327-6
M3 - Article
C2 - 33024575
AN - SCOPUS:85091202061
SN - 2058-7716
VL - 6
JO - Cell Death Discovery
JF - Cell Death Discovery
IS - 1
M1 - 90
ER -