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

Abstract

ABSTRACTMammalian 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, theAlrlocus 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 theMusgenome by gene conversion or an unequal recombination event a few million years ago.Ifi207has a large, distinctive repeat region that differs in sequence and length amongMusspecies and even closely related inbredMus musculusstrains. We show that IFI207 controls MLV infectionin vivoand 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. TheAlrlocus andIfi207provide 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). TheAlrgene family in mice has undergone rapid evolution in the last few million years and includes the creation of two novel members,MndaLandIfi207.Ifi207in 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.