FBXW7 is a multifaceted regulator of the innate immune response to DNA viruses.

Upon DNA virus infection, cGAS senses viral DNA and triggers MITA (also called STING)-dependent induction of type I interferons (IFN-Is) and other cytokines/chemokines. IFN-Is further activate STAT1/2 to induce interferon-stimulated genes (ISGs) and the innate antiviral response. How the innate antiviral response is silenced in uninfected cells and efficiently mounts upon viral infection is not fully understood. In this study, we found that FBXW7, a substrate recognition component of the SCF E3 ubiquitin ligase complex, is a multifaceted regulator of the innate immune response to DNA viruses. In uninfected cells, FBXW7 mediates the polyubiquitination and degradation of GSK3α/β-phosphorylated SLC35B2/3 at the Golgi apparatus. This leads to the downregulation of sulfated glycosaminoglycans (sGAGs) in the Golgi apparatus and the inactivation of MITA in uninfected cells. In addition, FBXW7 mediates the degradation of GSK3α/β-phosphorylated MYC, which is a repressor of STAT1/2, leading to proper STAT1/2 levels in uninfected cells. The differential regulation of FBXW7 on MITA and STAT1/2 ensures inactivation but is ready for fast mount of the innate immune response in uninfected cells. Infection with DNA viruses activates the PI3K‒AKT axis, which inactivates GSK3α/β and inhibits FBXW7-mediated polyubiquitination and degradation of SLC35B2/3, leading to increased production of sGAGs, activation of MITA and rapid onset of the innate antiviral response. Consistently, gene disruption experiments indicate that FBXW7 modulates the innate antiviral response in human THP-1 and mouse BMDM cells. These findings suggest that FBXW7 functions as a versatile regulator of the innate immune response to DNA viruses by differentially regulating upstream and downstream components of the type I interferon induction loop.