Small but mighty: ATG9A-positive vesicles are a branch of the intracellular nanovesicle superfamily.

The molecular and functional characterization of the thousands of uncoated intracellular transport vesicles inside cells is a major challenge. Intracellular nanovesicles (INVs) are a large and molecularly heterogenous family of uncoated transport vesicles, which are comprised of multiple subtypes. As a step to characterizing these subtypes, we recently published the first INV proteome and were intrigued by the enrichment of ATG9A in it. ATG9A is the only conserved transmembrane protein with a core function in macroautophagy/autophagy, and it is found on small, uncoated vesicles, termed "ATG9A-positive vesicles". We therefore, set out to disambiguate the relationship between these two types of vesicular carriers in cells. We showed that ATG9A-containing vesicles, rather than being a distinct vesicle class, represent one subset of the INV family. We also demonstrated that this relationship is functionally important and that perturbing INV-mediated trafficking impeded starvation-induced autophagy. Here, we briefly introduce INVs, summarize the evidence supporting our definition of ATG9A-flavor INVs and present our outlook on why we hope that this classification will help to consolidate efforts to understand the functions of these vesicles in autophagy and beyond.