The herpesviral antagonist m152 reveals differential activation of STING‐dependent IRF and NF‐κB signaling and STINGs dual role during MCMV infection

摘要

Cytomegaloviruses (CMVs) are master manipulators of the host immune response. Here, we reveal that the murine CMV (MCMV) protein m152 specifically targets the type I interferon (IFN) response by binding to stimulator of interferon genes (STING), thereby delaying its trafficking to the Golgi compartment from where STING initiates type I IFN signaling. Infection with an MCMV lacking m152 induced elevated type I IFN responses and this leads to reduced viral transcript levels both in vitro and in vivo. This effect is ameliorated in the absence of STING. Interestingly, while m152 inhibits STING‐mediated IRF signaling, it did not affect STING‐mediated NF‐κB signaling. Analysis of how m152 targets STING translocation reveals that STING activates style="fixed-case">NF‐κB signaling already from the style="fixed-case">ER prior to its trafficking to the Golgi. Strikingly, this response is important to promote early style="fixed-case">MCMV replication. Our results show that style="fixed-case">MCMV has evolved a mechanism to specifically antagonize the style="fixed-case">STING‐mediated antiviral style="fixed-case">IFN response, while preserving its pro‐viral style="fixed-case">NF‐κB response, providing an advantage in the establishment of an infection.