The ESCRT machinery counteracts Nesprin-2G-mediated mechanical forces during nuclear envelope repair

Abstract

Summary Transient nuclear envelope ruptures during interphase (NERDI) occur due to cytoskeletal compressive forces at sites of weakened lamina, and delayed NERDI repair results in genomic instability. Nuclear envelope (NE) sealing is completed by endosomal sorting complex required for transport (ESCRT) machinery. A key unanswered question is how local compressive forces are counteracted to allow efficient membrane resealing. Here, we identify the ESCRT-associated protein BROX as a crucial factor required to accelerate repair of the NE. Critically, BROX binds Nesprin-2G, a component of the linker of nucleoskeleton and cytoskeleton complex (LINC). This interaction promotes Nesprin-2G ubiquitination and facilitates the relaxation of mechanical stress imposed by compressive actin fibers at the rupture site. Thus, BROX rebalances excessive cytoskeletal forces in cells experiencing NE instability to promote effective NERDI repair. Our results demonstrate that BROX coordinates mechanoregulation with membrane remodeling to ensure the maintenance of nuclear-cytoplasmic compartmentalization and genomic stability.

Comprehensive analysis of the human ESCRT-III-MIT domain interactome reveals new cofactors for cytokinetic abscission

“…For example, CHMP7 is a specialized ESCRT-III protein that functions in post-mitotic closure and repair of the nuclear envelope ( Vietri et al, 2015 ; Gu et al, 2017 ; Olmos et al, 2015 ; von Appen et al, 2020 ; Denais et al, 2016 ; Thaller et al, 2019 ). Our observation that CHMP7 interacts exclusively with the MIT domain of the AMSH deubiquitinase supports the possibility that these events may be dynamically regulated by ubiquitin-dependent processes, as has been recently reported ( Wallis et al, 2021 ). More generally, our quantitative definition of the ESCRT-III-MIT interactome should provide a basis for probing how disruption of ESCRT-III and MIT cofactor activities can contribute to disease states such as hereditary spastic paraplegia ( Ciccarelli et al, 2003 ), or can be used therapeutically, for example in anti-cancer strategies based on VPS4 synthetic lethality ( Neggers et al, 2020 ; Szymańska et al, 2020 ).…”

Comprehensive analysis of the human ESCRT-III-MIT domain interactome reveals new cofactors for cytokinetic abscission

“…For example, CHMP7 is a specialized ESCRT-III protein that functions in post-mitotic closure and repair of the nuclear envelope(Vietri et al, 2015, Gu et al, 2017, Olmos et al, 2015, von Appen et al, 2020, Denais et al, 2016, Thaller et al, 2019). Our observation that CHMP7 interacts exclusively with the MIT domain of the AMSH deubiquitinase supports the possibility that these events may be dynamically regulated by ubiquitin-dependent processes, as has been recently reported(Wallis et al, 2021). More generally, our quantitative definition of the ESCRT-III-MIT interactome should provide a basis for probing how disruption of ESCRT-III and MIT cofactor activities can contribute to disease states such as hereditary spastic paraplegia(Ciccarelli et al, 2003), or can be used therapeutically, for example in anti-cancer strategies based on VPS4 synthetic lethality(Neggers et al, 2020, Szymanska et al, 2020).…”

Inhibition of Human Cytomegalovirus Particle Maturation by Activation of Liver X Receptor

“…The endosomal membranes are responsible for envelopment with the exchange of cellular organelle membranes in character during HCMV infection ( Mach et al, 2005 ; Tandon et al, 2009 ). Trans-Golgi network (TGN) and endoplasmic reticulum (ER)-Golgi intermediate compartments (ERGIC) also contribute to HCMV envelopment ( Calistri et al, 2007 ; Wallis et al, 2021 ). Similarly, viral proteins are predicted to employ several independent cellular pathways to accumulate into VAC during later stages of viral morphogenesis ( Crump et al, 2007 ; Jean Beltran et al, 2016 ).…”