# ANKFY1 bridges ATG2A-mediated lipid transfer from endosomes to phagophores

## TL;DR

ANKFY1 helps transfer lipids from endosomes to autophagosomes via ATG2A, revealing a new source of lipids for autophagosome formation.

## Contribution

Identifies ANKFY1 as a novel ATG2A-binding protein that facilitates lipid transfer from endosomes to phagophores.

## Key findings

- ANKFY1 depletion impairs autophagosome growth and reduces autophagy flux.
- ANKFY1 binds PI3P via its FYVE domain and enhances ATG2A-mediated lipid transfer.
- Endosomes serve as a new lipid source for phagophore expansion via ANKFY1 and ATG2A.

## Abstract

Macroautophagy is a process that cells engulf cytosolic materials by autophagosomes and deliver them to lysosomes for degradation. The biogenesis of autophagosomes requires ATG2 as a lipid transfer protein to transport lipids from existing membranes to phagophores. It is generally believed that endoplasmic reticulum is the main source for lipid supply of the forming autophagosomes; whether ATG2 can transfer lipids from other organelles to phagophores remains elusive. In this study, we identified a new ATG2A-binding protein, ANKFY1. Depletion of this endosome-localized protein led to the impaired autophagosome growth and the reduced autophagy flux, which largely phenocopied ATG2A/B depletion. A pool of ANKFY1 co-localized with ATG2A between endosomes and phagophores and depletion of UVRAG, ANKFY1 or ATG2A/B led to reduction of PI3P distribution on phagophores. Purified recombinant ANKFY1 bound to PI3P on membrane through its FYVE domain and enhanced ATG2A-mediated lipid transfer between PI3P-containing liposomes. Therefore, we propose that ANKFY1 recruits ATG2A to PI3P-enriched endosomes and promotes ATG2A-mediated lipid transfer from endosomes to phagophores. This finding implicates a new lipid source for ATG2A-mediated phagophore expansion, where endosomes donate PI3P and other lipids to phagophores via lipid transfer.