OASes and STING: adaptive evolution in concert.

Area of Science:

• Evolutionary biology
• Immunology
• Genetics

Background:

• 2'-5'-oligoadenylate synthases (OAS) and cyclic GMP-AMP synthase (cGAS) are crucial for detecting foreign nucleic acids and initiating antiviral responses.
• OAS activates RNase L upon double-stranded RNA binding, while cGAS activates STING upon double-stranded DNA binding.

Purpose of the Study:

• To investigate the evolutionary history of the OAS-RNASEL and cGAS-STING pathways in primates and bats.
• To identify sites under positive selection and understand their functional implications in antiviral immunity and drug response.

Main Methods:

• Comparative evolutionary analysis of OAS, RNase L, cGAS (MB21D1), and STING (TMEM173) genes.
• Phylogenetic analysis and population genetics studies in primates (humans, chimpanzees, gorillas).

Main Results:

• Evidence of widespread positive selection in both OAS-RNASEL and cGAS-STING axes in primates and bats.
• Positive selection identified at key residues in STING (residue 230) and RNase L, affecting ligand and drug responses and RNA preference.
• Parallel evolution observed in OAS1, OAS2, and MB21D1, suggesting selection pressures related to nucleic acid recognition and enzyme activation mechanisms.

Conclusions:

• Evolutionary adaptations in these antiviral pathways contribute to species-specific differences in infection susceptibility.
• Findings provide insights into the design of synthetic compounds as vaccine adjuvants by understanding host-pathogen interactions and drug targets.