Reovirus σ3 protein limits interferon expression and cell death induction

Induction of necroptosis by mammalian reovirus requires both type I interferon (IFN)-signaling and viral replication events that lead to production of progeny genomic dsRNA. The reovirus outer capsid protein {micro}1 negatively regulates reovirus-induced necroptosis by limiting RNA synthesis. To determine if the outer capsid protein {sigma}3, which interacts with {micro}1, also functions in regulating cell death, we used siRNA-mediated knockdown. Similar to that observed by diminishment of {micro}1 expression, knockdown of newly synthesized {sigma}3 enhances necroptosis. {sigma}3 knockdown does not impact reovirus RNA synthesis. Instead, this increase in necroptosis following {sigma}3 knockdown is accompanied by an increase in IFN production. Furthermore, ectopic expression of {sigma}3 is sufficient to block IFN expression following infection. Surprisingly, the capacity of {sigma}3 protein to bind dsRNA does not impact its capacity to diminish production of IFN. Consistent with this, infection with a virus harboring a mutation in the dsRNA binding domain of {sigma}3 does not result in enhanced production of IFN or cell death. Together, these data suggest that {sigma}3 limits the production of IFN to control innate immune signaling and cell death following infection through a mechanism that is independent of its dsRNA binding capacity. IMPORTANCEWe use mammalian reovirus as a model to study how virus infection modulates innate immune signaling and cell death induction. Here we sought to determine how viral factors regulate these processes. Our work highlights a previously unknown role for the reovirus outer capsid protein {sigma}3 in limiting the induction of a necrotic form of cell death called necroptosis. Induction of cell death by necroptosis requires production of interferon. {sigma}3 limits the induction of necroptosis by preventing excessive production of interferon following infection.