IFI207 promotes antiviral responses by modulating STING ubiquitination and degradation

Aim2-like receptors (ALRs) play crucial roles in innate immune signaling pathways and demonstrate strong positive selection likely driven by pathogens. IFI207, an ALR found in all <i>Mus</i> species, enhances interaction with and stabilization of STING, contributing to the control of Murine Leukemia Virus (MLV) infection. We show here that IFI207 enhances the type 1 interferon response by inhibiting activation-induced K63-linked ubiquitination of STING, thereby preventing its recognition by hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), a key component of the ESCRT complex, and its subsequent degradation in lysosomes. IFI207 promotes downstream signaling in the STING pathway in multiple cell types and moreover enhances the STING-dependent response to herpesvirus simplex 1 infection ex vivo and in vivo. We also show that IFI207 likely functions in dendritic cells to suppress MLV infection. Our study reveals that IFI207 acts as a modulator in the STING pathway, strengthening the host's defense against viral infections and suggests that the expansion of the <i>Alr</i> locus in mice may have occurred in response to endemic viruses.