Autophagy hijacked through viroporin-activated calcium/calmodulin-dependent kinase kinase-β signaling is required for rotavirus replication

Significance This study describes a unique mechanism of virus-initiated autophagy and exploitation of autophagy membranes for virus replication. Autophagy is a highly regulated cellular process in which cells destroy and recycle their own components in lysosomes. The mechanism most viruses use to induce autophagy is unknown. We show a rotavirus pore-forming protein activates a calcium-dependent signaling pathway to initiate autophagy. Rotavirus hijacks autophagy membranes to transport viral proteins to sites of virus replication for assembly of infectious particles and interferes with autophagy maturation. Inhibition of the signaling pathway blocks virus production, suggesting a therapeutic target to fight infection.