The mechanism of ESCRT-mediated surveillance of the nuclear envelope barrier

ESRT 介导的核膜屏障监测机制

• 批准号: 9923678
• 负责人: Charles Patrick Lusk
• 金额: $ 34.34万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923678
• 关键词: Active Biological Transport; Address; Affinity Chromatography; Amyotrophic Lateral Sclerosis; Binding Proteins; Biochemistry; Cell Differentiation process; Cell model; Cells; Complex; Cytolysis; DNA; Data; Diffusion; Electron Microscopy; Elements; Ensure; Eukaryotic Cell; Event; Family; Filament; Functional disorder; Future; Genetic; Genetic Transcription; Goals; Homo; Kinetics; Laboratories; Lead; Light; Link; Malignant Neoplasms; Mammalian Cell; Mediating; Membrane; Membrane Fusion; Membrane Proteins; Mind; Modeling; Molecular; Monitor; Morphology; Nerve Degeneration; Neurodegenerative Disorders; Nuclear; Nuclear Envelope; Nuclear Inner Membrane; Nuclear Outer Membrane; Nuclear Pore; Nuclear Pore Complex; Pathway interactions; Property; Proteins; Publishing; Quality Control; Rupture; Saccharomycetales; Scheme; Site; Sorting - Cell Movement; System; Tertiary Protein Structure; Toxic effect; Translations; Work; arm; cancer cell; cellular pathology; electron tomography; emerin; experimental study; human disease; member; nanobodies; nucleocytoplasmic transport; polymerization; reconstitution; recruit; seal; segregation; tool

Summary The discrete segregation of nuclear and cytosolic contents is a hallmark feature of all eukaryotic cells. It is achieved by the impermeability of the nuclear envelope membranes and the size-selective and active transport properties of nuclear pore complexes (NPCs), massive transport channels that span the nuclear envelope. Interestingly, it is becoming clear that there is a deleterious intermixing of cytosolic and nuclear contents in several human disease cell models where either NPC function or the integrity of the nuclear membranes is perturbed. Examples include the targeting of the nuclear transport machinery by the transcription and translation of hexanucleotide repeat expansions that are causative of neurodegenerative diseases, and nuclear rupture events observed in cancer cells. Through our work and others, we are discovering surveillance mechanisms that protect the nuclear compartment from aberrant NPCs and/or nuclear membrane ruptures. Indeed, we have discovered that even the “normal” remodeling of the nuclear envelope membranes during NPC assembly can, if not monitored, lead to a loss of nuclear-cytosolic compartmentalization. Here, we will use budding yeast as a model to determine the molecular mechanisms that govern the surveillance of de novo NPC assembly, which depends on the recruitment of the membrane bending and scission endosomal sorting required for transport (ESCRT) machinery to nascent NPC assembly sites. Our work is consistent with a model in which integral inner nuclear membrane proteins of the Lap2, emerin, MAN1 (LEM) domain family serve as adaptors to link defective NPC assembly intermediates to the ESCRTs, which seal off defective NPCs under a double membrane. In this proposal, we will pinpoint what step(s) in NPC assembly are under surveillance while defining the mechanism by which cells differentiate between functional and non-functional NPCs. The long term goal is to fully define and ultimately reconstitute the NPC assembly surveillance mechanism to illuminate fundamental mechanisms of quality control and membrane remodeling while providing a new conceptual framework to understand human disease mechanisms that present with disruptions in the nuclear envelope barrier.

总结