# Regulation of Autophagosome Membrane Dynamics by the Atg8 Family of Proteins

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $517,477

## Abstract

Macro-autophagy is the intracellular stress-response pathway by which the cell packages portions of
the cytosol for delivery into the lysosome. This “packaging” is carried out by the de novo formation of
a new organelle called the autophagosome that grows and encapsulates cytosolic material for eventual
lysosomal degradation. How autophagosomes form, including especially how the membrane
coordinates the capture of cytosolic toxins with its own expansion and closure is an area of intense
study. One factor implicated in both cargo-capture and autophagosome dynamics is the ubiquitin-like
protein, Atg8. During autophagy, Atg8 becomes covalently bound to phosphatidylethanolamine (PE)
on the preautophagosomal membrane and remains bound through the maturation process of the
autophagosome.
Our preliminary results suggest that Atg8-PE decorates the earliest autophagosome membrane
progenitor structure and plays an integral role in organizing the accumulation of membranes that
presages the eventual growth of the autophagosome itself. These activities depend upon the ability of
Atg8-PE to tether individual vesicles into an underlying support. Critically, Atg8 must remain associated
with the membranes throughout the growth of the autophagosome. Our results now also describe how
this pool of Atg8-PE is protected from recycling proteases that otherwise function to constitutively
remove Atg8 at other sites. Our discoveries are made possible by two important technological
advances. First, we have developed a variety of in vitro reconstitution approaches to study how Atg8-
PE and other autophagy proteins influence membrane deformation and structure. Second, we are now
able to image autophagosome intermediate structures at super resolution in three dimensions and
identify the same structures in micron deep electron tomograms revealing key features of the earliest
Atg8-decorated membranes.
With this proposal, we expect to demonstrate exactly how Atg8-PE proteins organize the proteins and
membranes that support autophagosome membrane expansion.

## Key facts

- **NIH application ID:** 10051183
- **Project number:** 2R01GM100930-09
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Thomas James Melia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $517,477
- **Award type:** 2
- **Project period:** 2013-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051183

## Citation

> US National Institutes of Health, RePORTER application 10051183, Regulation of Autophagosome Membrane Dynamics by the Atg8 Family of Proteins (2R01GM100930-09). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10051183. Licensed CC0.

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