Autophagy and exosomes play different roles in the disposal of unwanted cellular materials.

Degradative autophagy supplies a source of nutrients and energy by digesting cytoplasmic components. Additionally, it eliminates toxic protein aggregates and defective organelles from cells. Exosomes are small vesicles that are released by cells into the extracellular environment and are also involved in maintenance of homeostasis by removing unwanted materials and intracellular pathogens. Nevertheless, it remains unclear how these two processes may differ or are alike in their roles in maintaining intracellular homeostasis. In this study, we found that secretory exosomes served as a quality control mechanism, maintaining intracellular RNA homeostasis by facilitating both the selective packaging of endogenous and exogenous RNA species. Conversely, autophagic degradation primarily functions to dispose of both endogenous and exogenous proteins, resulting in controlling intracellular proteostasis. The depletion of exosome secretion resulted in prolonged accumulation of exogenous RNA within the cells, whereas it had no significant effect on the accumulation of exogenous proteins. Viral infection not only induced the host autophagy response, but also impacted secretion of exosomes. Our data showed that secretory exosomes contributed to the clearing of increased intracellular microRNAs induced by enterovirus infection, thereby weakening viral replication. Furthermore, the secretory exosomes were essential for the disposal of viral RNA replicon rather than autophagic degradation, thereby facilitating host survival. Our results collectively revealed that both secretory exosome and autophagic degradation were crucial for maintaining cellular homeostasis, but that they operate through distinct mechanisms and dispose of different types of unwanted materials.