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- Title
OASes and STING: Adaptive Evolution in Concert.
- Authors
Mozzi, Alessandra; Pontremoli, Chiara; Forni, Diego; Clerici, Mario; Pozzoli, Uberto; Bresolin, Nereo; Cagliani, Rachele; Sironi, Manuela
- Abstract
OAS(20--50-oligoadenylate synthases)proteinsandcyclicGMP--AMPsynthase (cGAS,genesymbol:MB21D1)patrol thecytoplasm 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, amajor determinant of response to natural ligands and tomimetic drugs (e.g., DMXAA),was positively selected in Primates and Chiroptera. In both orders, selection also targeted an a-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, andMB21D1 revealed parallel evolution, with the corresponding residues being selected indifferent genes. Asthis cannot result fromgene 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.
- Subjects
OLIGOADENYLATE synthetase; INTERFERONS; RIBONUCLEASE L; ENZYME activation; PHYLOGENY; CYTOPLASM
- Publication
Genome Biology & Evolution, 2015, Vol 7, Issue 4, p1016
- ISSN
1759-6653
- Publication type
Article
- DOI
10.1093/gbe/evv046