# Autophagosome closure by the ESCRT machinery

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2020 · $312,315

## Abstract

Project Summary/Abstract
 During macroautophagy (hereafter referred to as autophagy), a crescent-shaped membrane known as
the phagophore elongates to engulf damaged cargo and seals to generate a double-membrane vesicle called
the autophagosome. While much of the core machinery regulating autophagy induction and phagophore
nucleation and elongation has been identified, the machinery for phagophore closure is largely unknown. The
goal of this application is to define the molecular mechanism by which the phagophore seals to generate the
completed autophagosome. Phagophore closure is a critical step in autophagy that is required for lysosomal
fusion and efficient degradation and recycling of autophagic cargo. The sealing of phagophores has
misguidedly been described as a membrane fusion event when the process of generating the inner and outer
autophagosomal membrane actually requires membrane scission. Notably, the topology of phagophore closure
is similar to ESCRT (endosomal sorting complexes required for transport)-mediated scission, in which the
ESCRT machinery mediates membrane fission from within the membrane neck. While ESCRT defects
accumulate immature autophagosomal structures in C. elegans, Drosophila and mammals, a molecular
understanding for the phenotype remains unclear. Exploiting the topology of LC3 during autophagosome
biogenesis, we established a novel HaloTag-LC3 based assay to differentiate phagophores, autophagosomes
and autolysosomes. Using this assay, we have identified ESCRT-III as a candidate regulator of phagophore
closure. We hypothesize that phagophore-associated factors assemble a novel adaptor for the recruitment and
assembly of ESCRT-III filaments for phagophore closure. We will test our hypotheses in the following Specific
Aims: (1) to define the core ESCRT machinery required for phagophore closure; (2) to identify the upstream
factor(s) that serve as an autophagy-specific adaptor for ESCRT-III assembly during phagophore closure.

## Key facts

- **NIH application ID:** 9884792
- **Project number:** 5R01GM127954-03
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** HONG-GANG WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $312,315
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9884792

## Citation

> US National Institutes of Health, RePORTER application 9884792, Autophagosome closure by the ESCRT machinery (5R01GM127954-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9884792. Licensed CC0.

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