The ESCRT machinery counteracts Nesprin-2G-mediated mechanical forces during nuclear envelope repair.
The ESCRT machinery counteracts Nesprin-2G-mediated mechanical forces during nuclear envelope repair.
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DOI：
10.1016/j.devcel.2021.10.022
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发表时间：
2021-12-06
影响因子：
11.8
通讯作者：
Agromayor M
中科院分区：
文献类型：
--
作者：
Wallis SS;Ventimiglia LN;Otigbah E;Infante E;Cuesta-Geijo MA;Kidiyoor GR;Carbajal MA;Fleck RA;Foiani M;Garcia-Manyes S;Martin-Serrano J;Agromayor M
间期一过性核膜破裂(NERDI)是由于细胞骨架受压而导致的，延迟的NERDI修复导致基因组不稳定。核膜(NE)的密封由运输所需的内体分选复合体(ESCRT)机械完成。一个关键的悬而未决的问题是，如何抵消局部压力，以实现有效的薄膜再密封。在这里，我们确定ESCRT相关蛋白Brox是加速NE修复所需的关键因素。关键的是，Brox结合了Nesprin-2G，Nesprin-2G是核骨架和细胞骨架复合体(LINC)的连接物。这种相互作用促进了Nesprin-2G泛素化，并促进了断裂部位压缩肌动蛋白纤维施加的机械应力的松弛。因此，Brox在经历NE不稳定的细胞中重新平衡过多的细胞骨架力量，以促进有效的NERDI修复。我们的结果表明，Brox将机械调节与膜重塑协调起来，以确保核质区域化和基因组稳定性的维持。施加在细胞核上的细胞骨架力可以使其膜破裂，Brox被ESCRT膜重塑机制招募到断裂部位，Brox泛素化LINC复合体蛋白Nesprin-2G，靶向它的降解Brox协调机械应力的局部松弛与膜重塑核膜(NE)的完整性对于保护基因组免受损害至关重要。Wallis等人。研究NE在破裂的情况下如何修复。研究表明，Brox被ESCRT局部招募，并通过对Nesprin-2G的作用帮助重新密封破裂的膜来减少细胞骨架压力
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. Cytoskeletal forces exerted on the nucleus can rupture its membrane BROX is recruited to sites of rupture by the ESCRT membrane remodeling machinery BROX ubiquitinates the LINC complex protein Nesprin-2G, targeting it for degradation BROX coordinates local relaxation of mechanical stress with membrane remodeling Nuclear envelope (NE) integrity is essential to protect the genome from damage. Wallis et al. investigate how the NE is repaired in case of rupture. The study demonstrates that BROX is locally recruited by ESCRTs and reduces cytoskeletal stress through its action on Nesprin-2G to help reseal the ruptured membrane
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DOI：
10.1126/science.aba2894
发表时间：
2020-10-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lomakin AJ;Cattin CJ;Cuvelier D;Alraies Z;Molina M;Nader GPF;Srivastava N;Sáez PJ;Garcia-Arcos JM;Zhitnyak IY;Bhargava A;Driscoll MK;Welf ES;Fiolka R;Petrie RJ;De Silva NS;González-Granado JM;Manel N;Lennon-Duménil AM;Müller DJ;Piel M
通讯作者：
Piel M
影响因子：
3.5
作者：
De Vos, Winnok H.;Houben, Frederik;Broers, Jos L. V.
通讯作者：
Broers, Jos L. V.
影响因子：
64.5
作者：
Atilla-Gokcumen GE;Muro E;Relat-Goberna J;Sasse S;Bedigian A;Coughlin ML;Garcia-Manyes S;Eggert US
通讯作者：
Eggert US
影响因子：
5.7
作者：
Agromayor, Monica;Soler, Nicolas;Caballe, Anna;Kueck, Tonya;Freund, Stefan M.;Allen, Mark D.;Bycroft, Mark;Perisic, Olga;Ye, Yu;McDonald, Bethan;Scheel, Hartmut;Hofmann, Kay;Neil, Stuart J. D.;Martin-Serrano, Juan;Williams, Roger L.
通讯作者：
Williams, Roger L.
DNA损伤遵循修复因子耗竭，并预测孔迁移后癌细胞的基因组变异。
DOI：
10.1016/j.cub.2016.11.049
发表时间：
2017-01-23
期刊：
Current biology : CB
影响因子：
--
作者：
Irianto J;Xia Y;Pfeifer CR;Athirasala A;Ji J;Alvey C;Tewari M;Bennett RR;Harding SM;Liu AJ;Greenberg RA;Discher DE
通讯作者：
Discher DE