# The mechanism of nuclear autophagy

> **NIH NIH R56** · YALE UNIVERSITY · 2022 · $343,209

## Abstract

Project Summary
Over the last 10 years, the lysosome-mediated degradation pathway macroautophagy has gained prominence
in the study of aging-related disorders and extension of lifespan. Macroautophagy is an essential cellular
pathway responsible for the elimination of cytosolic proteins, lipids and organelles, and as such, the field has
focused upon the role of macroautophagy in clearing protein aggregates or dysfunctional organelles (such as
mitochondria) that specifically accumulate in the cytoplasm. Increasingly however, protein accumulation and
organelle dysfunction are observed to occur within the nucleus, apparently shielded from cytoplasmic
processes by the double-membraned nuclear envelope. Furthermore, links between aging and nuclear
envelope structural defects are emerging, including nuclear envelopathies caused by mutations in the
envelope scaffolding lamins and associated integral inner nuclear membrane proteins. How the cell responds
to these nuclear insults is not well understood, but there is emerging evidence that components of the nuclear
envelope and the nucleus are subject to macroautophagy-dependent turnover. Thus, it is clear that we must
refocus our attention on how nuclear quality control is executed and specifically on the mechanism(s) that
governs nuclear content turnover in cytoplasmic autophagosomes. Thus, in this proposal, we focus on the
fundamental question of how cytoplasmic autophagy machinery and nuclear envelope remodeling are
coordinated. Using S. cerevisiae, where discovery of the molecular machinery driving nuclear autophagy is the
most mature and where we have generated substantial preliminary and recently published data, we will test an
exciting “outside-in” model of nucleophagy. This model invokes a novel translumenal bridge that spans the
nuclear envelope membranes and connects the cytosol to the nucleus. This proposal will thus fully define the
molecular components that make up this nucleophagy pathway and place these factors within an ultrastructural
timeline. Elements of this pathway will then be reconstituted using fully engineered in vitro systems in order to
collectively provide critical molecular insight into the key membrane remodeling events necessary to remove
nuclear contents while maintaining nuclear integrity. With the completion of this project, we will further our
mechanistic understanding of a key underappreciated macroautophagic process and open doors to define how
nuclear autophagy can impact aging-impaired proteostasis.

## Key facts

- **NIH application ID:** 10688323
- **Project number:** 1R56AG071201-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Charles Patrick Lusk
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $343,209
- **Award type:** 1
- **Project period:** 2022-09-30 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10688323

## Citation

> US National Institutes of Health, RePORTER application 10688323, The mechanism of nuclear autophagy (1R56AG071201-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10688323. Licensed CC0.

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