The Role of Interferon-inducible Protein 207 in Innate Immunity

The Aim2-like receptors (ALRs) are a family of proteins found in most mammalian species that have several roles in innate immunity. ALRs detect pathogen or self-nucleic acids found in both the cytoplasm and the nucleus. Through binding nucleic acids, ALRs initiate innate immune signaling pathways which activate production of type I interferons or inflammasome assembly and proinflammatory cell death. During infection, these responses help the host control pathogen replication. The ALRs are encoded at a single genetic locus; however, the number of ALR genes varies in different species. For example, depending on the strain, mice have 13-16 Alr genes. We investigated the Alr loci in three inbred mouse strains, C57BL/6, DBA/2J, and 129P2. We defined the composition of genes in the Alr loci of these mice and identified a highly polymorphic Alr, Ifi207, among the three strains. We found that Ifi207 has a large, unique repeat region that differs in its sequence and length in inbred laboratory and wild mice. To test the function of IFI207 as an innate immune sensor and to determine the function of the repeat region, we used overexpression, knockdown, and knockout mouse studies. We found that the IFI207 repeat region is required for stabilization of STING, an innate immune adaptor downstream of several DNA sensors such as cGAS, IFI16, IFI203, and DDX41 that coordinates innate immune responses to foreign DNA. First, we determined that IFI207 proteins with more repeats more effectively bound and stabilized STING. When IFI207 was depleted, STING-dependent responses to cGAMP, nucleic acids, and murine leukemia virus (MLV) were diminished. Finally, we showed that IFI207 controls MLV infection in vivo. These studies suggest that selective pressures such as those from pathogens like MLV may have caused the expansion and diversification of ALR genes in mice and other mammalian species.