LEM2 phase separation promotes ESCRT-mediated nuclear envelope reformation
LEM2 phase separation promotes ESCRT-mediated nuclear envelope reformation
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DOI：
10.1038/s41586-020-2232-x
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发表时间：
2020-04-29
期刊：
影响因子：
64.8
通讯作者：
Frost, Adam
中科院分区：
文献类型：
--
作者：
von Appen, Alexander;LaJoie, Dollie;Frost, Adam
细胞分裂后，跨膜接头LEM 2的相分离确保ESCRT机制重塑微管并密封核膜。在细胞分裂期间，核膜的重塑使有丝分裂纺锤体能够分离染色体（1）。密封细胞核的重组需要ESCRT（转运所需的内体分选复合物）和LEM 2（一种跨膜ESCRT衔接子）（2-4）。在这里，我们展示了LEM 2在微管上凝聚的能力如何控制ESCRT的激活和协调纺锤体的解体。LEM 2的LEM基序结合BAF，赋予LEM 2对染色质的亲和力（5，6），而邻近的低复杂性结构域（LCD）促进LEM 2相分离。LCD内富含脯氨酸精氨酸的序列与微管结合，并靶向LEM 2向穿过新生核膜的纺锤体微管的冷凝。此外，LEM 2的翼状螺旋结构域激活ESCRT-II/ESCRT-III杂合蛋白CHMP 7以形成共寡聚环。人类细胞中这些事件的破坏阻止了下游ESCRT的募集，损害了纺锤体的解体，并导致核完整性和DNA损伤的缺陷。我们提出，在核重组LEM 2冷凝成一个液体样的阶段和coassembles与CHMP 7形成一个大分子的O型环密封膜，染色质和纺锤体之间的汇合处。这里描述的LEM 2的特性，以及相关的内核膜蛋白的同源结构（7，8），表明相分离可能有助于其他关键的包膜功能，包括间期修复（8-13）和染色质组织（14-17）。
Following cell division, phase separation of the transmembrane adaptor LEM2 ensures that the ESCRT machinery remodels microtubules and seals the nuclear envelope.During cell division, remodelling of the nuclear envelope enables chromosome segregation by the mitotic spindle(1). The reformation of sealed nuclei requires ESCRTs (endosomal sorting complexes required for transport) and LEM2, a transmembrane ESCRT adaptor(2-4). Here we show how the ability of LEM2 to condense on microtubules governs the activation of ESCRTs and coordinated spindle disassembly. The LEM motif of LEM2 binds BAF, conferring on LEM2 an affinity for chromatin(5,6), while an adjacent low-complexity domain (LCD) promotes LEM2 phase separation. A proline-arginine-rich sequence within the LCD binds to microtubules and targets condensation of LEM2 to spindle microtubules that traverse the nascent nuclear envelope. Furthermore, the winged-helix domain of LEM2 activates the ESCRT-II/ESCRT-III hybrid protein CHMP7 to form co-oligomeric rings. Disruption of these events in human cells prevented the recruitment of downstream ESCRTs, compromised spindle disassembly, and led to defects in nuclear integrity and DNA damage. We propose that during nuclear reassembly LEM2 condenses into a liquid-like phase and coassembles with CHMP7 to form a macromolecular O-ring seal at the confluence between membranes, chromatin and the spindle. The properties of LEM2 described here, and the homologous architectures of related inner nuclear membrane proteins(7,8), suggest that phase separation may contribute to other critical envelope functions, including interphase repair(8-13) and chromatin organization(14-17).