LINC complex protein nesprin-2 has pro-apoptotic activity via Bcl-2 family proteins

Liora Lindenboim, Hila Zohar, Gregg G. Gundersen, Howard J. Worman, Reuven Stein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The apoptotic intrinsic pathway is initiated by perforation of the mitochondrial outer membrane by the effector pro-apoptotic proteins of the Bcl-2 family, Bax and Bak. Bax and Bak need to be activated, a process facilitated by the action of BH3-only pro-apoptotic members of the Bcl-2 family. The latter either directly activates the effector proteins or antagonizes the action of pro-survival Bcl-2 family members such as Bcl-xL. The nuclear envelope is a known target of the apoptotic machinery; however, it may also act as mediator of apoptosis. We showed previously that the nuclear envelope protein nesprin-2, a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex, can bind to Bax in close proximity to the mitochondria and that the binding increases in apoptotic cells. We now show that depleting nesprin-2 inhibits the apoptotic mitochondrial pathway as measured by Bax and Bak activation and cytochrome c release. This survival effect was Bcl-xL-dependent. Nesprin-2 depletion also inhibited spontaneous exposure of the N-terminus of Bak in cells lacking Bcl-xL and increased the presence of Bcl-xL and Bax in the mitochondria. These results indicate that nesprin-2 promotes Bak activation and regulates mitochondrial translocation/retrotranslocation of Bcl-2 family proteins. Our findings demonstrate a new apoptotic pathway whereby the nuclear envelope, via nesprin-2, regulates apoptosis.

Original languageEnglish
Article number29
JournalCell Death Discovery
Volume10
Issue number1
DOIs
StatePublished - Dec 2024

Funding

FundersFunder number
National Institutes of Health
National Institute on AgingR01AG064944
National Institute of General Medical SciencesR35 GM136403
United States - Israel Binational Science Foundation
United States-Israel Binational Science Foundation2019204

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