Cells contain a myriad of vesicle types with distinct behaviours and functions. Intracellular nanovesicles (INVs), collectively marked by the membrane protein TPD54, are a recently described family of small, uncoated vesicles that move mainly via diffusion. Many subtypes or ‘flavours’ of INVs appear to exist and participate in various trafficking processes. In this study (Fesenko et al., 2025), the Royle lab report the first INV proteome and explore whether ATG9A vesicles, small vesicles involved in autophagosome biogenesis, are in fact a flavour of INV. The INV proteome shows overlap with proteomes from synaptic vesicles, synaptic-like microvesicles (SLMVs) and ATG9A vesicles, which are particularly enriched for TPD54. To determine whether TPD54-containing vesicles also contain ATG9A and vice versa, the authors ‘trap’ each vesicle type by relocalising them to mitochondria and observe how the other vesicle marker responds. Trapping of TPD54 also relocalises the bulk of ATG9A vesicles, whereas trapping of ATG9A only affects a fraction of TPD54 vesicles, suggesting that ATG9A vesicles are a specific subset of INV. Moreover, trapping of INVs relocalises several proteins established to be ATG9A vesicle cargoes. ATG9A vesicles are thought to function as ‘seeds’ for growing phagophores, and the authors indeed observe that TPD54 depletion dampens autophagy in starved cells. Together, these data indicate that ATG9A vesicles represent a new INV flavour and implicate INVs in autophagic regulation.

Read the paper here.

Read the interview with first author Mary Fesenko.