VAMP7-Dependent Autophagic Secretion Allows for Axonal Growth in Nutrient Restriction Conditions

VAMP7 is involved in autophagy and exocytosis mediating neurite growth, two yet unconnected cellular pathways. Here we show the occurrence of combined VAMP7/ATG9 secretory events. VAMP7/LC3- and VAMP7/ATG9-positive vesicles moved anterogradely along the axon towards growth cones. Electron microscopy showed that VAMP7 knockout disrupted the amphisome branch of the autophagic response. Autophagic secretion was impaired in VAMP7-knockout cells and autophagy-deficient cells were impaired in VAMP7-mediated exocytosis. Secretomics showed that VAMP7-knockout cells were deficient in unconventional secretion of cytoplasmic, exosomal, mitochondrial and LC3 interacting region-containing proteins suggesting that VAMP7 is required for amphisome secretion. In addition, autophagy stimulated neurite growth in a VAMP7-dependent manner, and neurons still grew long axons in nutrient-restricted and autophagy conditions. A nanobody directed against VAMP7 inhibited the axonal growth induced by nutrient restriction. We propose that VAMP7-dependent secretion of amphisomes allows for axonal growth in nutrient restriction conditions inducing autophagy.