# Molecular mechanisms of autophagosome biogenesis

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $443,929

## 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:** 9972376
- **Project number:** 2R01GM092740-10
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Takanori Otomo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $443,929
- **Award type:** 2
- **Project period:** 2010-12-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972376

## Citation

> US National Institutes of Health, RePORTER application 9972376, Molecular mechanisms of autophagosome biogenesis (2R01GM092740-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9972376. Licensed CC0.

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