A novel viral regulatory network for autophagy induction: Respiratory Syncytial Virus NS2 protein regulates autophagy by modulating BECN1 ISGylation and protein stability.

Respiratory syncytial virus, or RSV, is a leading cause of viral pneumonia and bronchiolitis in children and other susceptible populations. RSV infection dysregulates the immune response leading to exaggerated inflammation in the airway. Among other responses, RSV induces macroautophagy/autophagy, a key process that regulates immune response during infection. We investigated the molecular mechanisms underlying RSV-induced autophagy and showed that the RSV nonstructural NS2 protein promotes autophagy using a dual mechanism. First, NS2 interacts with and stabilizes the autophagy regulator BECN1 (beclin 1), augmenting its intracellular availability for autophagy induction. Second, NS2 interferes with BECN1 ISGylation, thus restricting the intracellular pool of the anti-autophagy ISGylated form of BECN1. Thus, the viral protein (i.e., NS2)-autophagy-ISGylation axis represents a yet unknown regulatory network for viruses. As many viruses induce autophagy that shapes virus-associated immune responses including inflammation, exploring viral protein-autophagy-ISGylation regulatory networks can aid in developing interventions to curb exaggerated immune responses such as inflammation for treating virus-associated inflammatory diseases.