Cytoplasmic Shift of Interferon Regulatory Factors Co‐Evolved With Jawed Vertebrate Innate Immunity

The emergence of jaws in early vertebrates introduced a novel feeding apparatus and powerful oral defenses, but it also increased the risk of physical injury and pathogen exposure. Interferon regulatory factors (IRFs) play critical roles in orchestrating innate immunity and inflammation in response to invading microbes and tissue damage, with their subcellular localization being essential to some IRFs' function. Our results indicate that IRF members underwent independent expansion and diversification in two distinct vertebrate lineages: jawed and jawless vertebrates. The jawed vertebrate-specific factor, IRF5, has maintained conserved nuclear export sequences throughout evolution, while newly diversified IRF members in jawed vertebrates have acquired cytoplasmic localization. This cytoplasmic shift particularly affected IRFs involved in type I interferon (IFN) signaling (IRF3, IRF5, IRF7, and IRF9), suggesting co-evolution with the development of the type I IFN system in jawed animals. Interestingly, although IRF9 is inherently nuclear, its association with Signal Transducer and Activator of Transcription 2 (STAT2) has led to its cytoplasmic localization. Additionally, IRF6, another jawed vertebrate-specific factor, plays a crucial role in jaw development, reflecting an evolutionary adaptation that aligns structural innovations with immune function. Our findings suggest that the evolution of jaws coincided with the adoption of cytoplasmic localization in IRF members, potentially enhancing rapid immune responses to meet the immunological challenges posed by the predatory lifestyle of early jawed vertebrates.