# ATG2 transfers lipids from ER exit site membranes to directly expand the growing autophagosome

> **NIH NIH F31** · YALE UNIVERSITY · 2022 · $46,752

## Abstract

Project Summary/Abstract
Macroautophagy (hereafter autophagy) is a cellular degradative process that is intimately connected to the
process of aging. Autophagy maintains cell health and homeostasis through the delivery of potentially cytotoxic
cargo to the lysosome through the de novo formation of the double membrane autophagosome.
This process is impaired with increased age. Furthermore, deletion of the core autophagy genes has been
shown in multiple organisms to decrease lifespan, while rescue experiments conversely restore a full lifespan.
Autophagy is especially critical in maintaining the health of long-lived neurons, and defects in autophagy result
in various neurodegenerative diseases, including Parkinson’s Disease, Alzheimer’s Disease, and amyotrophic
lateral sclerosis. Autophagy protein ATG2 is essential to this process and tissue-specific ablation of this protein
results in decreased lifetime, motility, and age-related tissue deterioration. We recently demonstrated that
ATG2 is a lipid transfer protein with a novel structure that allows for bulk lipid delivery. This activity is essential
for autophagosome biogenesis. I predict that ATG2 delivers lipids directly into the nascent autophagosome to
expand the growing membrane. As-of-yet, the identity of the lipid-donating organelle is not known. Intriguingly,
a mechanism to deliver a net transfer of lipids in one direction is without clear precedent in mammalian biology.
As this mechanism likely depends on the biophysical properties of both membranes, I propose to formally
identify the donor membrane from which ATG2 extracts lipids. This project is designed to provide the training
necessary to achieve a future career in independent research. Furthermore, as this project will elucidate
the membrane source for this critical age-delaying cell biological process, this body of research will identify
key regulators of autophagy that represent additional methods of age-related therapeutic intervention.
In this proposal, I seek to understand the mechanism by which ATG2 delivers a net transfer of lipids into the
autophagosome by addressing three main questions. First, what is the donor membrane for autophagosome
biogenesis? I propose to leverage the non-biased and high resolution APEX strategy of proximity labeling with
live cell fluorescent microscopy to formally identify the donor membrane. Strikingly, preliminary data reveal that
ATG2 resides at ER exit sites (ERES) during autophagosome biogenesis, a highly specialized subdomain of
the ER. Second, does ATG2 lipid transfer possess intrinsic directionality, or does it rely upon local membrane
energetics? I have developed two in vitro lipid transfer assays to mimic the ERES-autophagosome contact site,
through which I can assess the directionality and specificity of lipid transfer through bulk-ensemble
measurement and by visual examination. Third, how is ATG2 recruited to the donor membrane? Following
identification of the donor membrane, I can now s...

## Key facts

- **NIH application ID:** 10536404
- **Project number:** 1F31AG079606-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Devin Fuller
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536404

## Citation

> US National Institutes of Health, RePORTER application 10536404, ATG2 transfers lipids from ER exit site membranes to directly expand the growing autophagosome (1F31AG079606-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10536404. Licensed CC0.

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