OASes and STING: Adaptive Evolution in Concert

Abstract

OAS (2′–5′-oligoadenylate synthases) proteins and cyclic GMP–AMP synthase (cGAS, gene symbol: MB21D1) patrol the cytoplasm for the presence of foreign nucleic acids. Upon binding to double-stranded RNA or double-stranded DNA, OAS proteins and cGAS produce nucleotide second messengers to activate RNase L and STING (stimulator of interferon genes, gene symbol: TMEM173), respectively; this leads to the initiation of antiviral responses. We analyzed the evolutionary history of the MB21D1–TMEM173 and OAS–RNASEL axes in primates and bats and found evidence of widespread positive selection in both orders. In TMEM173, residue 230, a major determinant of response to natural ligands and to mimetic drugs (e.g., DMXAA), was positively selected in Primates and Chiroptera. In both orders, selection also targeted an α-helix/loop element in RNase L that modulates the enzyme preference for single-stranded RNA versus stem loops. Analysis of positively selected sites in OAS1, OAS2, and MB21D1 revealed parallel evolution, with the corresponding residues being selected in different genes. As this cannot result from gene conversion, these data suggest that selective pressure acting on OAS and MB21D1 genes is related to nucleic acid recognition and to the specific mechanism of enzyme activation, which requires a conformational change. Finally, a population genetics-phylogenetics analysis in humans, chimpanzees, and gorillas detected several positively selected sites in most genes. Data herein shed light into species-specific differences in infection susceptibility and in response to synthetic compounds, with relevance for the design of synthetic compounds as vaccine adjuvants.

DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway

“…This particular SNP is the second most frequent in the population, and has been previously reported as a loss-of-function human STING variant where it exhibits greater than 90% loss in the ability to induce IFNβ production 63 There are 6 positively selected amino acids of STING in bats, with 3 of these residues located in the transmembrane domain that are important for protein dimerization 64 . It has also been found that residue 230 in primate and bat phylogenies is undergoing positive selection.…”

“…It has also been found that residue 230 in primate and bat phylogenies is undergoing positive selection. This site is also polymorphic in the human population as G230A, and the residue is located in the loop region of STING, which is predicted to form a lid that covers the CDN binding pocket 64 . 68,71 .…”

Epigenetic regulation of OAS2 shows disease-specific DNA methylation profiles at individual CpG sites

“…The OAS2 protein is a well-known innate immune activated antiviral enzyme catalyzing synthesis of 2′-5′-oligoadenylate for RNase L activation and inhibition of viral propagation9. More recent studies show that it also participates in other biological processes.…”

Functional evolution of the OAS1 viral sensor: Insights from old world primates

“…The residue that exhibits the most variation across primates is residue 54, which has been shown to be under positive selection in human, chimpanzee, and gorilla as well as under balancing selection in chimpanzee and macaque (Ferguson, et al 2012; Fish and Boissinot 2015; Mozzi, et al 2015). In OWM, ancestral Arg predominates followed in commonality by Cys and lastly His and Tyr.…”

“…selection in favor of amino acid changes. Evolutionary analyses across Primates and Chiroptera have reported accelerated evolution of OAS genes, particularly for OAS1 (Hancks, et al 2015; Mozzi, et al 2015). Moreover, house mouse, chimpanzee, and macaque populations have been shown to harbor an extremely high level of polymorphism at OAS1 denoting the action of balancing selection at this locus (Ferguson, et al 2012; Ferguson, et al 2008; Fish and Boissinot 2015).…”