2023
Autophagy

ATG9 resides on a unique population of small vesicles in presynaptic nerve terminals

Authors:

Beyenech Binotti, Momchil Ninov, Andreia P. Cepeda, Marcelo Ganzella, Ulf Matti, Dietmar Riedel, Henning Urlaub, Sivakumar Sambandan, Reinhard Jahn

Keywords:

autophagy, autophagosome, ATG9, AP2-complex, vesicle, synapse

Abstract:

In neurons, autophagosome biogenesis occurs mainly in distal axons, followed by maturation during retrograde transport. Autophagosomal growth depends on the supply of membrane lipids which requires small vesicles containing ATG9, a lipid scramblase essential for macroautophagy/autophagy. Here, we show that ATG9-containing vesicles are enriched in synapses and resemble synaptic vesicles in size and density. The proteome of ATG9-containing vesicles immuno-isolated from nerve terminals showed conspicuously low levels of trafficking proteins except of the AP2-complex and some enzymes involved in endosomal phosphatidylinositol metabolism. Super resolution microscopy of nerve terminals and isolated vesicles revealed that ATG9-containing vesicles represent a distinct vesicle population with limited overlap not only with synaptic vesicles but also other membranes of the secretory pathway, uncovering a surprising heterogeneity in their membrane composition. Our results are compatible with the view that ATG9-containing vesicles function as lipid shuttles that scavenge membrane lipids from various intracellular membranes to support autophagosome biogenesis.