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

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $343,375

## Abstract

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.

## Key facts

- **NIH application ID:** 9923678
- **Project number:** 5R01GM105672-08
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Charles Patrick Lusk
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,375
- **Award type:** 5
- **Project period:** 2013-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923678

## Citation

> US National Institutes of Health, RePORTER application 9923678, The mechanism of ESCRT-mediated surveillance of the nuclear envelope barrier (5R01GM105672-08). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9923678. Licensed CC0.

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