Enya, T. | Search bioRxiv

bioRxiv2026

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 Mus 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 hosts defense against viral infections and suggests that the expansion of the Alr locus in mice may have occurred in response to endemic viruses.

immunology↗

bioRxiv2024

IFI207, a young and fast-evolving protein, controls retroviral replication via the STING pathway

Mammalian AIM-2-like receptor (ALR) proteins bind nucleic acids and initiate production of type I interferons or inflammasome assembly, thereby contributing to host innate immunity. In mice, the Alr locus is highly polymorphic at the sequence and copy number level and we show here, is one of the most dynamic regions of the genome. One rapidly evolving gene within this region, Ifi207, was introduced to the Mus genome by gene conversion or an unequal recombination event a few million years ago. Ifi207 has a large, distinctive repeat region that differs in sequence and length among Mus species and even closely related inbred Mus musculus strains. We show that IFI207 controls MLV infection in vivo and that it plays a role in the STING-mediated response to cGAMP, dsDNA, DMXXA and MLV. IFI207 binds to STING and inclusion of its repeat region appears to stabilize STING protein. The Alr locus and Ifi207 provide a clear example of the evolutionary innovation of gene function, possibly as a result of host-pathogen co-evolution. IMPORTANCEThe Red Queen hypothesis predicts that the arms race between pathogens and the host may accelerate evolution of both sides, and therefore cause higher diversity in virulence factors and immune-related proteins, respectively (1). The Alr gene family in mice has undergone rapid evolution in the last few million years and includes the creation of two novel members, MndaL and Ifi207. Ifi207 in particular became highly divergent, with significant genetic changes between highly related inbred mice. IFI207 protein acts in the STING pathway and contributes to anti-retroviral resistance via a novel mechanism. The data show that under the pressure of host-pathogen coevolution in a dynamic locus, gene conversion and recombination between gene family members creates new genes with novel and essential functions that play diverse roles in biological processes.

immunology↗