Evolution and emergence of primate‐specific interferon regulatory factor 9

Abstract

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 primatespecific 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.

The Co-Evolution of Jawed Vertebrates and Interferon Regulatory Factor 5 Generates Unique Inflammation and Innate Immunity

“…Our data indicates that IRF5, 6, and surprisingly IRF4 and 8 first emerged in cartilaginous fishes, coinciding with the appearance of a primitive type I IFN system (Secombes and Zou, 2017). Considering various analyses, including ours and others (Angeletti et al, 2020; Drury et al, 2023; Huang et al, 2010; Kasamatsu et al, 2010; Nehyba et al, 2009), it appears that IRF3-9 have likely not been identified in Cephalochordata (lancelets), Urochordata (tunicates), Agnatha (lampreys), or other jawless vertebrates. In jawed vertebrates starting with cartilaginous fishes, IRF3-9 were present, leading to a significant expansion of the IRF family.…”

Quick guide to evolutionary medicine in neuroimmunomodulation: Why “evolved for the benefit of the species” is not a valid argument

“…When all conditions are met, the genetic composition of the population will automatically change over time, which is evolution (there are additional mechanisms like drift that also cause changes in the gene pool and as such evolution, but these will not be reviewed here). For example, individuals can express a new anti-viral supporter of a cytokine signalling pathway such as the IFN regulatory factor 9 [30] that allows them to better cope with infection, live longer, and reproduce more. Consequently, more copies of the underlying gene variant will be transmitted to the next generation compared to the alternative variant.…”

Exploration of the Noncoding Genome for Human-Specific Therapeutic Targets—Recent Insights at Molecular and Cellular Level

“…One example is interleukin 8 (IL8), which emerged as one of the most strongly deregulated genes in peripheral blood mononuclear cells (PBMCs) after human myocardial infarction [8,10,50] but does not exist in mice, the most used animal model in cardiovascular research. Drury et al [51], investigating the evolution and emergence of interferon regulatory factor 9 (IRF9), a key component of the ISGF3 complex and the cellular innate immune response, identified primate-specific IRF9 (PS-IRF9) isoforms unique to old world monkeys and great apes. Ellwanger et al [52] analyzed the function of the primate-specific NLRP11 gene product and found it highly expressed in human immune cells (myeloid cells, B cells, lymphoma lines).…”