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Virus-induced autophagic degradation of STAT2 as a mechanism for interferon signaling blockade

Avia, Miguel; Rojas, Jose M.; Miorin, Lisa; Pascual, Elena; Rijn, P.A. van; Martin, Veronica; Garcia-Sastre, Adolfo; Sevilla, Noemi

Abstract

The mammalian interferon (IFN) signaling pathway is a primary component of the innate antiviral response, and viral pathogens have evolved multiple mechanisms to antagonize this pathway and to facilitate infection. Bluetongue virus (BTV), an orbivirus of the Reoviridae family, is transmitted by midges to ruminants and causes a disease that produces important economic losses and restriction to animal trade and is of compulsory notification to the World Organization for Animal Health (OIE). Here, we show that BTV interferes with IFN‐I and IFN‐II responses in two ways, by blocking STAT1 phosphorylation and by degrading STAT2. BTV‐NS3 protein, which is involved in virion egress, interacts with STAT2, and induces its degradation by an autophagy‐dependent mechanism. This STAT2 degradative process requires the recruitment of an E3‐Ub‐ligase to NS3 as well as NS3 K63 polyubiquitination. Taken together, our study identifies a new mechanism by which a virus degrades STAT2 for IFN signaling blockade, highlighting the diversity of mechanisms employed by viruses to subvert the IFN response.