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.

核包膜（NE）是包裹真核细胞基因组的双层膜屏障，物理上保护遗传物质不受细胞质环境的影响。这就产生了一种选择性屏障，可以调节两个隔室之间蛋白质的运输。在每次有丝分裂过程中，NE在前期被拆除，以允许复制染色体的适当分离，然后在后期/末期在两个新生细胞核周围重新组装。尽管激酶/磷酸酶启动和维持有丝分裂的电路已被很好地定义，但如何微调后的有丝分裂事件以实现完整和及时的NE封闭仍然不清楚。我将结合遗传学、蛋白质组学、细胞生物学和成像方法来阐明ESCRT-III机制是如何通过有丝分裂退出过程中NE重组位点的磷酸化/去磷酸化事件和蛋白质-蛋白质相互作用来调节的。了解指导核重组的机械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，以确保在每个细胞周期中及时和功能性的核细胞质区隔。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对基因组稳定性构成威胁。由于ESCRT-III解除调控可导致NE完整性受损，并最终导致核区室化的丧失，因此对ESCRT-III蛋白在空间和时间上的作用的更深入了解不仅可以揭示潜在病理的细胞机制的新见解，还可以揭示新的治疗方法。