# Establishing a Mechanism for the Autophagic Degradation of Nuclear Components and its Relationship to Aging

> **NIH NIH F31** · YALE UNIVERSITY · 2023 · $46,563

## Abstract

Project Summary/Abstract
Autophagy is a protective cellular mechanism with the capacity to maintain organelle homeostasis and thereby
delay cellular and organismal aging. Interestingly, recent work suggests that degradation of components of the
nucleus may be important for maintaining chronological lifespan (CLS). Consistent with this, there are many
long-standing genetic links between the nucleus, and components of its bounding membranes, with aging.
Thus, a priority for the field is to fully understand the nuclear autophagy (nucleophagy) mechanism to more
fully define how clearance of nuclear components contributes to aging and age-related disease. However,
there is no defined nuclear cargo adaptor in mammals making isolating the role of nucleophagy from
autophagy more challenging. By contrast, a nucleophagy cargo adaptor, Atg39, has been identified in budding
yeast providing an opportunity to investigate the nucleophagy mechanism and its role in maintaining CLS in
this model organism. Key questions include which proteins are required for nucleophagy and how the nuclear
envelope (NE) is remodeled to generate a subdomain of the nucleus competent for capture by
autophagosomes. The goal of this proposal is to define key mechanistic steps in nucleophagy and provide
insight into its potential role in slowing aging. I will achieve these goals by using proximity-labeling and Mass
Spectrometry to identify proteins that cooperate with Atg39 to drive nucleophagy. The contribution of these
proteins to nucleophagy will be determined by measuring nucleophagic flux in targeted gene deletions as well
as colocalization experiments using live-cell fluorescence microscopy, which will inform the spatial and
temporal dynamics of the function of each protein. The second aim will utilize an innovative combination of
Bimolecular Fluorescence Complementation (BiFC) and Correlative Light Electron Microscopy (CLEM) to study
the steps of nucleophagy at the resolution of the ultrastructure.

## Key facts

- **NIH application ID:** 10673748
- **Project number:** 5F31AG069490-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Philip Mannino
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $46,563
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-08-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10673748

## Citation

> US National Institutes of Health, RePORTER application 10673748, Establishing a Mechanism for the Autophagic Degradation of Nuclear Components and its Relationship to Aging (5F31AG069490-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10673748. Licensed CC0.

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