Autophagic extracellular vesicles: a distinct secretory route linking autophagy to extracellular communication

Macroautophagy/autophagy is classically defined as a degradative pathway that delivers cytoplasmic material to lysosomes. However, accumulating evidence indicates that autophagy can also support unconventional secretion. A recent study identifies a previously unrecognized subtype of small extracellular vesicles termed autophagic extracellular vesicles (AEVs). These vesicles originate from amphisomes formed by the fusion of autophagosomes with multivesicular bodies and are characterized by a size below 100 nm together with the presence of autophagic cargos, ESCRT-III components and RAB13. Importantly, biogenesis of AEVs is distinct from that of classical exosomes, which requires specific components of the ESCRT III complex and the GTPase RAB27A. The further finding that enterovirus can exploit AEVs to infect receptor-negative cells, thereby expanding viral tropism, suggests that secretory autophagy serves as a pivotal mechanism driving pathogen dissemination. This work provides the conceptual framework of extracellular vesicle heterogeneity and positions secretory autophagy as an important contributor to intercellular communication.