# Molecular mechanisms of autophagosome biogenesis

> **NIH NIH R01** · SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE · 2023 · $130,345

## Abstract

Abstract
The catabolic process known as autophagy is essential for the maintenance of cellular health and the removal
of cytotoxins, such as aberrant macromolecules, damaged organelles, and invasive bacteria. The hallmark of
autophagy is de novo formation of the double-membrane vesicle called autophagosome. The process begins
with assembling the precursor membrane phagophore adjacent to the endoplasmic reticulum (ER), followed
by its expansion into a cup-like shape around a non-selective portion of the cytoplasm or a selected
cytotoxin. During the expansion, the edges of the phagophore remain associated with the ER and at the last
moment, the edges merge, resulting in the closure of the cup, thereby producing a complete
autophagosome. The contribution to cellular homeostasis by autophagy hinges on the fact that the
phagophore can engulf degradation substrates. For the phagophore to achieve this remarkable task, it must
expand. We and others have made progress toward the goal of understanding the molecular mechanism of
phagophore expansion by determining the function of ATG2, the largest protein in the group of autophagy-
related proteins. We have worked on human ATG2A and demonstrated that this protein is a rod-shaped
membrane tether that can transfer lipids between membranes. Our current working model is that ATG2
transports lipids from the ER to the phagophore by tethering them. The transported lipids would then serve
as the building blocks the phagophore built around the substrates. This new proposal aims to build on this
model and gain further mechanistic insights into this enigmatic process. In Aim 1, we will extend our study of
ATG2 to determine its structure. The goal is to explain how ATG2 transports lipids between membranes. In
Aim 2, we will focus on ATG9, the integral membrane protein of autophagy that has been known as an ATG2
interactor. Through structural and biochemical characterizations, we aim to elucidate the function of this
protein and gain new insights into phagophore expansion. In Aim 3, we will characterize the interaction
between ATG2 and ATG9. The goal is to determine how these two proteins interact with each other at the
structural level and explore the significance of the interaction for ATG2-mediated lipid transfer and
phagophore expansion. Results from these studies will vertically advance our understanding of
autophagosome biogenesis at the molecular level.

## Key facts

- **NIH application ID:** 10799467
- **Project number:** 3R01GM092740-14S1
- **Recipient organization:** SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE
- **Principal Investigator:** Takanori Otomo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $130,345
- **Award type:** 3
- **Project period:** 2010-12-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10799467

## Citation

> US National Institutes of Health, RePORTER application 10799467, Molecular mechanisms of autophagosome biogenesis (3R01GM092740-14S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10799467. Licensed CC0.

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