Coxsackievirus B3 induces crosstalk between autophagy and apoptosis to benefit its release after replicating in autophagosomes through a mechanism involving caspase cleavage of autophagy-related proteins.

Coxsackievirus B3 (CVB3) is known to induce both autophagy and apoptosis, but whether a relationship exists between these processes upon infection, and whether and how they influence the viral life cycle are currently unknown. We observed here that while autophagosome formation increased in CVB3-infected HeLa cells at the early stage of infection, it decreased at the late stage of infection along with increased apoptosis. Examining whether a functional relationship existed between autophagy and apoptosis during CVB3 infection, we found that increasing levels of autophagy inhibited apoptosis and that some apoptotic proteins in the endogenous and exogenous apoptosis pathways played a role in the transition from autophagy to apoptosis by cleaving the autophagy-related proteins Beclin-1 and Atg5. However, the transcription and translation of full-length Atg5 and Beclin-1 also increased, which likely counteracted the cleavage effect in order to prevent cells from dying too early and to ensure that CVB3 replication was complete in the autophagosomes. Using pharmacological inducers and inhibitors of autophagy as well as inhibitors of apoptosis, we found that while CVB3 replication relied on the autophagosomes, its release from the cell depended on apoptosis. Therefore, autophagy and apoptosis are two important processes that interact with each other during CVB3 infection, promoting the CVB3 life cycle.