Evolution and Emergence of Primate-specific Interferon Regulatory Factor 9

The binding of interferon (IFN) to its receptors leads to formation of IFN-stimulated gene factor 3 (ISGF3) complex that activates the transcription of cellular IFN-regulated genes. IFN regulatory factor 9 (IRF9, also called ISGF3γ or p48) is a key component of ISGF3. However, there is limited knowledge regarding the molecular evolution of IRF9 among vertebrates. In this study, we have identified the existence of the IRF9 gene in cartilaginous fish (sharks). Among primates, several isoforms unique to old world moneys and great apes are identified. These IRF9 isoforms are named as primate-specific IRF9 (PS-IRF9) to distinguish from canonical IRF9. PS-IRF9 originates from a unique exon usage and differential splicing in the IRF9 gene. Although the N-terminus are identical for all IRF9s, the C-terminal regions of the PS-IRF9 are completely different from canonical IRF9. In humans, two PS-IRF9s are identified and their RNA transcripts were detected in human primary peripheral blood mononuclear cells. In addition, human PS-IRF9 proteins were detected in human cell lines. Sharing the N-terminal exons with the canonical IRF9 proteins, PS-IRF9 is predicted to bind to the same DNA sequences as the canonical IRF9 proteins. As the C-terminal regions of IRFs are the determinants of IRF functions, PS-IRF9 may offer unique biological functions and represent a novel signaling molecule involved in the regulation of the IFN pathway in a primate-specific manner.