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Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins
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 wi...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501853/ https://www.ncbi.nlm.nih.gov/pubmed/33024575 http://dx.doi.org/10.1038/s41420-020-00327-6 |
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author | Lindenboim, Liora Grozki, Dan Amsalem-Zafran, Ayelet R. Peña-Blanco, Aida Gundersen, Gregg G. Borner, Christoph Hodzic, Didier Garcia-Sáez, Ana J. Worman, Howard J. Stein, Reuven |
author_facet | Lindenboim, Liora Grozki, Dan Amsalem-Zafran, Ayelet R. Peña-Blanco, Aida Gundersen, Gregg G. Borner, Christoph Hodzic, Didier Garcia-Sáez, Ana J. Worman, Howard J. Stein, Reuven |
author_sort | Lindenboim, Liora |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7501853 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-75018532020-10-05 Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins Lindenboim, Liora Grozki, Dan Amsalem-Zafran, Ayelet R. Peña-Blanco, Aida Gundersen, Gregg G. Borner, Christoph Hodzic, Didier Garcia-Sáez, Ana J. Worman, Howard J. Stein, Reuven Cell Death Discov Article 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. Nature Publishing Group UK 2020-09-18 /pmc/articles/PMC7501853/ /pubmed/33024575 http://dx.doi.org/10.1038/s41420-020-00327-6 Text en © The Author(s) 2020 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Lindenboim, Liora Grozki, Dan Amsalem-Zafran, Ayelet R. Peña-Blanco, Aida Gundersen, Gregg G. Borner, Christoph Hodzic, Didier Garcia-Sáez, Ana J. Worman, Howard J. Stein, Reuven Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins |
title | Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins |
title_full | Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins |
title_fullStr | Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins |
title_full_unstemmed | Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins |
title_short | Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins |
title_sort | apoptotic stress induces bax-dependent, caspase-independent redistribution of linc complex nesprins |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501853/ https://www.ncbi.nlm.nih.gov/pubmed/33024575 http://dx.doi.org/10.1038/s41420-020-00327-6 |
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