The 4EHP/GIGYF2 translation repressor complex is co-opted by the vaccinia virus K3L protein as a potential mechanism of immunoevasion

Poxviruses have evolved robust immunoevasion strategies to facilitate replication in the cytosol. We previously reported that like several RNA viruses, vaccinia virus replication is impaired in the absence of the host cap-binding translation repressor protein 4EHP (eIF4E2), implicating the latter in host antiviral defense regulation and immunosuppression. Here, we show that the vaccinia virus-encoded K3L protein interacts with 4EHP via its obligatory binding partner GIGYF2 to increase the stability of the 4EHP/GIGYF2 complex. Consequently, K3L bolsters 4EHP/GIGYF2-mediated mRNA translation repression. Thus, we demonstrate that a 4EHP/GIGYF2-mediated mechanism is exploited by and conserved among RNA and DNA viruses as a potential immunoevasion strategy. Our findings document a 4EHP/GIGYF2-dependent stringent regulation of infection by poxviruses, a clinically important family of viruses that are employed as vaccine vectors and in oncolytic viral therapy.