Evolution and emergence of primate-specific interferon regulatory factor 9

Area of Science:

• Immunology
• Molecular Biology
• Evolutionary Biology

Background:

• Interferon (IFN) binding to receptors activates the IFN-stimulated gene factor 3 (ISGF3) complex, crucial for regulating IFN-inducible genes.
• Interferon regulatory factor 9 (IRF9) is a key component of the ISGF3 complex.
• Limited information exists on the molecular evolution of IRF9 across vertebrate species.

Purpose of the Study:

• To investigate the molecular evolution of the IRF9 gene in vertebrates.
• To identify and characterize novel IRF9 isoforms in primates.

Main Methods:

• Bioinformatic analysis to identify IRF9 gene existence in cartilaginous fish.
• Identification and characterization of unique IRF9 isoforms in primates, termed primate-specific IRF9 (PS-IRF9).
• Analysis of exon usage and differential splicing in the IRF9 gene to understand PS-IRF9 origins.
• Detection of PS-IRF9 RNA transcripts and proteins in human cells.

Main Results:

• The IRF9 gene was identified in cartilaginous fish (sharks).
• Several primate-specific IRF9 (PS-IRF9) isoforms, arising from unique exon usage and differential splicing, were identified in Old World monkeys and great apes.
• PS-IRF9 isoforms share identical N-terminal regions with canonical IRF9 but possess distinct C-terminal regions.
• Two PS-IRF9 isoforms were identified in humans, with their RNA transcripts detected in peripheral blood mononuclear cells and proteins found in cell lines.
• PS-IRF9 proteins are predicted to bind the same DNA sequences as canonical IRF9 due to shared N-terminal exons.

Conclusions:

• The study identified IRF9 in cartilaginous fish, expanding knowledge of its vertebrate evolution.
• Novel primate-specific IRF9 (PS-IRF9) isoforms were discovered, originating from alternative splicing of the IRF9 gene.
• These PS-IRF9 variants, with distinct C-terminal regions, may confer unique biological functions and represent novel signaling molecules in the primate-specific IFN pathway.