Marek’s disease virus serine/threonine kinase Us3 facilitates viral replication by targeting IRF7 to block IFN-β production

Abstract

Marek’s disease virus (MDV) is a highly oncogenic alphaherpesvirus that induces malignant T-cell lymphomas in chickens, leading to great economic loss in poultry industry. The unique-short kinase 3 (Us3), a serine/threonine kinase encoded by three MDV types (MDV-1, MDV-2 and HVT), is important for MDV replication. However, the mechanism of Us3 facilitating MDV replication has not been completely elucidated. In the present study, we report that Us3 significantly facilities MDV replication via inhibition of β interferon (IFN-β) production at the late phase of MDV infection. Overexpression or interference of Us3 significantly promoted or inhibited the replication of MDV, and accordingly inhibited or promoted the expression of IFN-β. Further, Us3 was shown to suppresses interferon stimulatory DNA (ISD)-triggered IFN-β production by targeting IFN regulatory factor 7 (IRF7) rather than NF-κB signaling. Moreover, Us3 but not kinase-dead (KD) Us3 mutant K220A blocked the nuclear translocation of IRF7 by inhibiting dimerization. Importantly, Us3 phosphorylated and interacted with IRF7. Furthermore, Us3-deficient MDV weakened viral replication and increased IFN-β production in infected cells or chickens. These results indicated that Us3 interrupts the cytosolic DNA sensing pathway, thereby leading to inhibition of IFN-β production by targeting IRF7, promoting MDV replication. Our finding expands the knowledge about the role of Us3 in MDV replication.