The capping arms race: evolutionary interplay between IFIT proteins and viral molecular mimicry

Effective host survival during viral infection depends on the ability to discriminate endogenous messenger RNA from pathogenic RNA species. Interferon-induced proteins with tetratricopeptide repeats (IFITs) constitute a central component of this defence system, functioning as specialised cytosolic RNA surveillance proteins that detect molecular features characteristic of non-self transcripts. This review examines the dynamic evolutionary interplay between IFIT-mediated antiviral restriction and viral evasion strategies. IFIT proteins recognise defined chemical and structural determinants at the RNA 5' terminus-including 5'-triphosphorylated ends and the absence of 2'-O-methylation-and sequester such transcripts to inhibit viral translation. In response, RNA viruses have evolved sophisticated evasion strategies, including the encoding or acquisition of 2'-O-methyltransferases, exploitation of host cap-modifying enzymes, and cap-snatching mechanisms that generate host-like cap 1 and m⁶Am signatures to evade immune recognition. Beyond the canonical antiviral roles attributed to IFIT1 and IFIT5, accumulating evidence indicates that IFIT2 and IFIT3 function as critical regulatory components within IFIT complexes, stabilising protein-protein interactions, modulating RNA-binding affinity, and influencing downstream signalling pathways. Collectively, these concepts position IFIT proteins as RNA surveillance proteins and regulatory scaffolds within innate immunity. We propose that future antiviral strategies should focus on unmasking viral RNA, thereby restoring its detection by the host innate immune system.