Journal of Molecular BiologyVolume 437, Issue 18, 15 September 2025, 169288Author links open overlay panel, Highlights•

ATG9 is an essential autophagy related protein involved in autophagosome biogenesis.

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ATG9 is a lipid scramblase, delivery vesicle, and a platform for autophagy initiation.

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ATG9 vesicles originate from the trans-Golgi Network.

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The autophagy-independent functions of ATG9 rely on the trafficking of ATG9.

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ATG9 functions independently of autophagy in plasma membrane protection, Golgi heat stress response and lysosome homeostasis.

Abstract

Autophagy proteins coordinate the biogenesis of a phagophore, the formation and maturation of an autophagosome. Genetic mutations of these proteins can result in dysregulated autophagy, stalled autophagosome biogenesis, and lead to cell death. ATG9, the sole transmembrane ATG (autophagy related) protein governs the nucleation of the phagophore. At a molecular level ATG9 has been shown to be a lipid scramblase capable of redistributing lipids across the lipid bilayer. ATG9-positive vesicles can also deliver lipid-modifying enzymes to alter the lipid composition of membranes. Both functions are required for autophagy. However, ATG proteins, including ATG9, play key molecular roles in pathways unrelated to autophagy. ATG9 has been shown to function in multiple pathways at the Golgi, plasma membrane, and lysosomes. ATG9 can also play an important role in immune signalling. The trafficking of ATG9 in ATG9-positive vesicles is essential to many of these pathways. In this review we highlight the functions of ATG9 in autophagy and autophagy-unrelated pathways, here referred to as “non-canonical functions”, and summarise the broader role of ATG9A in cell homeostasis.

Graphical abstractDownload: Download high-res image (300KB)Download: Download full-size imageKeywords

Atg9

ATG9A

autophagy

membrane trafficking

AbbreviationsAP

Adaptor Protein Complex

BEACH

Beige and Chediak Higashi

CASM

Conjugation of ATG8 to single membranes

EBSS

Earle’s buffer saline solution

FIP200

200kD FAK family kinase interacting protein

FTS-Hook-FHIP

fused toes homolog-Hook-FHIP

HDIR

Horma Domain Interacting Region

INV

intracellular nanovesicles

BLTP

Bridge-like lipid Transfer Protein

LAP

LC3-associated phagocytosis

LLOMe

L-Leucyl-L-leucine methyl ester

LRBA

LPS responsive beige-like anchor

MAPK

Mitogen Activated protein kinase

NCOA4

nuclear receptor coactivator 4

PAMP

pathogen-associated molecular patterns

PAS

preautophagosome structure

PE

phosphatidylethanolamine

PI4K

phosphatidylinositol-4 kinases

RNPs

ribonuclear particles

ROS

Reactive Oxygen Species

SCAMP3

secretory carrier membrane protein 3

SCV

Salmonella Containing Vacuole

SRC

protein-oncogene tyrosine protein kinase Src

TNFR

tumour necrosis factor receptor

ULK1/ULK2

Unc-51-like kinase 1/2

© 2025 The Author(s). Published by Elsevier Ltd.