Interferon regulatory factor 5 (IRF5) is a key transcription factor regulating inflammatory cytokines and interferons, with its dysregulation linked to autoimmune and inflammatory diseases. Pseudogenes can exhibit gene regulatory functions. This study investigates the human IRF5 pseudogene 1 (IRF5P1) and its potential role in primate-specific innate immunity. We find that IRF5P1 is a chimeric processed pseudogene containing sequences derived from multiple sources and is specific to higher primates, such as apes and humans. Our analyses suggest that IRF5P1 arose through an ancient retroviral integration event, incorporating an IRF5-like sequence from a disparate organism. Interestingly, IRF5P1 resides within the triple QxxK/R motif containing (TRIQK) gene, and its antisense strand is predominantly expressed as part of the TRIQK pre-mRNA. We propose that the antisense IRF5P1 RNA may regulate IRF5 expression through complementary binding to the IRF5 mRNA, with variants in the IRF5 gene potentially modulating this interaction. The conservation of IRF5P1 in the primate lineage suggests its positive effects on primate evolution and innate immunity. This study highlights the importance of investigating pseudogenes and their potential regulatory roles in shaping lineage-specific immune adaptations.

The emergence of jaws in early vertebrates introduced a novel feeding apparatus and potent oral defenses but also increased the risk of physical injury and pathogen exposure. Innate immunity and inflammation constitute the body’s first line of defense against invading microbes and tissue damage, aiming to eliminate threats and restore internal homeostasis. Interferon regulatory factor 5 (IRF5) plays a critical role in orchestrating innate immunity and inflammation by regulating the transcription of genes that encode type I interferons (IFNs) and pro-inflammatory cytokines. As the closest member of IRF5, IRF6 is involved in jaw development in humans and mice. However, the evolution of IRF5 and IRF6 has remained poorly understood. We have identified the IRF5 and IRF6 genes in cartilaginous fish, including sharks. As cartilaginous fish represent one of the oldest surviving jawed vertebrate lineages, the presence of these genes suggests that they have ancient origins potentially dating back hundreds of millions of years to early jawed vertebrates. Furthermore, our analysis shows that IRF5 has conserved nuclear export sequences and phosphorylation sites for activation throughout evolution from cartilaginous fish to humans, indicating that these regulatory elements evolved early and have been maintained across jawed vertebrates. Additionally, the shift in the subcellular localization of IRF5 from the nucleus to the cytosol, and of other interferon-related IRFs, aligns with functional enhancements of IRFs in innate immunity and the emergence of IFNs across jawed vertebrates. This analysis implies that the evolution of jaws may have driven the emergence of new IRF members, the expansion of their functions, and the development of a unique inflammation and innate immune system in vertebrates.