NEPhos_Phosphoregulation of ESCRT-III during nuclear envelope reformation

NEPhos_ESCRT-III 核膜重构过程中的磷酸调节

• 批准号: EP/Z00098X/1
• 负责人: Jeremy Carlton
• 金额: $ 24.5万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2025
• 资助国家: 英国
• 起止时间: 2025 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FZ00098X%2F1
• 关键词: NEPhos_Phosphoregulation; ESCRT; III; during; nuclear

The nuclear envelope (NE) is a double membrane barrier which encloses the genome of eukaryotic cells, physically shielding the genetic material from the cytoplasmic environment. This creates a selective barrier that regulates the trafficking of proteins between the two compartments. During each mitosis, the NE is dismantled in prophase to allow the proper segregation of the duplicated chromosomes and then reassembled around the two nascent nuclei in late anaphase/telophase. Even though the circuitry of kinases/ phosphatase initiating and sustaining mitosis is well defined, how the latter mitotic events are fine-tuned to achieve a complete and timely NE sealing are still ill-understood. I will use a combination of genetic, proteomic, cellular biology and imaging approaches to shed light on how the ESCRT-III machinery is regulated by phosphorylation/dephosphorylation events and protein-protein interactions at sites of NE reformation during mitotic exit. Understanding the mechanistical aspects guiding nuclear reassembly will allow a better understanding of how mitotic exit events are coordinated in space and time to ensure a timely and functional nucleocytoplasmic compartmentalisation at every cell cycle. Moreover, NE defects are a known cause of disease, as chromatin exposure to the cytoplasmic milieu poses a threat to genome stability. Since ESCRT-III deregulation can lead to an impairment of NE integrity and eventually to a loss of nuclear compartmentalisation, a deeper understanding of how ESCRT-III proteins act in space and time could reveal not only new insights in the cellular mechanisms underlying pathology but also new therapeutical approaches.

核膜（NE）是一个双层膜屏障，包围着真核细胞的基因组，从物理上屏蔽遗传物质免受细胞质环境的影响。这形成了调节两个区室之间蛋白质运输的选择性屏障。在每次有丝分裂期间，NE 在前期被拆除，以允许复制的染色体正确分离，然后在后期/末期围绕两个新生核重新组装。尽管激酶/磷酸酶启动和维持有丝分裂的电路已经明确，但如何微调后者的有丝分裂事件以实现完整且及时的 NE 封闭仍不清楚。我将结合遗传、蛋白质组学、细胞生物学和成像方法来阐明 ESCRT-III 机制如何受到有丝分裂退出期间 NE 重组位点的磷酸化/去磷酸化事件和蛋白质-蛋白质相互作用的调节。了解指导核重组的机制方面将有助于更好地理解有丝分裂退出事件如何在空间和时间上协调，以确保每个细胞周期及时且功能性的核细胞质区室化。此外，NE 缺陷是已知的疾病原因，因为染色质暴露于细胞质环境会对基因组稳定性构成威胁。由于 ESCRT-III 失调会导致 NE 完整性受损，并最终导致核区室化丧失，因此更深入地了解 ESCRT-III 蛋白在空间和时间上的作用不仅可以揭示病理学基础细胞机制的新见解，还可以揭示新的治疗方法。