Inhibition of the DNA-Sensing pathway by pseudorabies virus UL24 protein via degradation of interferon regulatory factor 7

Abstract

The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway plays an important role in the innate immune response by the production of type I interferon (IFN) against DNA virus infection. However, viruses have evolved a variety of strategies to antagonize the host antiviral response to facilitate infection and replication. Pseudorabies virus (PRV), a DNA virus that causes great economic losses to the swine industry, encodes approximate 70 proteins, including some that are involved in evasion of host immunity. However, the mechanism employed by PRV to regulate type I IFN remains unclear. The results of the present study showed that the transcription levels of type I IFN were significantly upregulated by a UL24-deleted PRV strain. Furthermore, IFN-β activation induced by poly(dA:dT) or stimulated by cGAS-STING was inhibited by UL24 overexpression in PK15 cells. Co-immunoprecipitation analysis demonstrated that UL24 interacts with and can degrade interferon regulatory factor 7 (IRF7) through the proteasome pathway in a dose-dependent manner. Together, these results showed that PRV UL24 interacted with IRF7 via the proteasome pathway and antagonized cGAS-STING-mediated activation of IFN-β.