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

Abstract

Infections with viral pathogens impose considerable selective pressure on host defensive genes. Those genes at the forefront, responsible for identifying and binding exogenous molecular viral components, will carry the hallmarks of this struggle. Oligoadenylate synthetase (OAS) enzymes play a major role in the innate defense against a large number of viruses by acting as sensors of viral infections. Following their up-regulation by the interferon pathway, OASs bind viral dsRNA and then signal ribonuclease L (RNase L) to degrade RNA, shutting down viral and host protein synthesis. We have investigated the evolution of OAS1 in twenty-two Old World monkey species. We identified a total of 35 codons with the earmarks of positive selection and we performed a comprehensive analysis of their functional significance using in silico modeling of the OAS1 protein. Subdividing OAS1 into functional domains revealed intense purifying selection in the active domain but significant positive directional selection in the RNA-binding domain (RBD), the region where OAS1 binds viral dsRNA. The modeling analysis revealed a concentration of rapidly evolving residues in one region of the RBD suggestive of the sub-functionalization of different regions of the RBD. This analysis also identified several positively selected residues circumscribing the entry to the active site suggesting adaptive evasion of viral antagonism and/or selection for production of oligoadenylate of different length.

RNA regulation of the antiviral protein 2′‐5′‐oligoadenylate synthetase

“…As a result of these host defense systems, viruses have evolved diverse countermeasures to either mask their RNAs or to limit (or exploit) the effectiveness of specific PRRs and thus evade detection. recent evolutionary adaptation driven specifically by OAS's role as an innate immune sensor in higher organisms (Fish & Boissinot, 2016;Hu et al, 2018;Kjaer et al, 2009). In terms of its properties as an RNA-binding protein, OAS also appears quite distinct: it does not contain a canonical dsRNA-binding domain or other RNA recognition motif but instead recognizes dsRNA through a patch of positively charged amino acids located on the protein's surface.…”

“…As described further below, dsRNA binding to OAS results in unique structural rearrangements necessary to form the enzyme active site and promote synthesis of 2‐5A (Donovan, Dufner, & Korennykh, ). This requirement appears to be a relatively recent evolutionary adaptation driven specifically by OAS's role as an innate immune sensor in higher organisms (Fish & Boissinot, ; Hu et al, ; Kjaer et al, ). In terms of its properties as an RNA‐binding protein, OAS also appears quite distinct: it does not contain a canonical dsRNA‐binding domain or other RNA recognition motif but instead recognizes dsRNA through a patch of positively charged amino acids located on the protein's surface.…”

“…In terms of its properties as an RNA‐binding protein, OAS also appears quite distinct: it does not contain a canonical dsRNA‐binding domain or other RNA recognition motif but instead recognizes dsRNA through a patch of positively charged amino acids located on the protein's surface. Notably, this dsRNA binding surface is absent in OAS proteins in lower organisms that lack interferon signaling (Fish & Boissinot, ; Hu et al, ). This mode of dsRNA recognition by OAS is also distinct from other well‐studied innate immune sensors of dsRNA, like retinoic acid‐inducible gene I (RIG‐I) or dsRNA‐activated protein kinase (PKR) (Devarkar et al, ; Hornung et al, ; Manche, Green, Schmedt, & Mathews, ; Nallagatla, Toroney, & Bevilacqua, , ), and suggests that OAS proteins might have only very weak discriminatory ability between different dsRNA sequences.…”

Recurrent loss-of-function mutations reveal costs to OAS1 antiviral activity in primates

“…OAS1 amino acid sequence is also highly variable across species. Phylogenetic and population genetic analysis demonstrate that OAS1 has evolved under recurrent positive selection in primates and other mammals, resulting in remarkable sequence diversity [17][18][19] . A lack of comparative studies of OAS1 activity, however, leaves the functional consequences of OAS1 evolution unknown.…”

The Immune Responses of the Animal Hosts of West Nile Virus: A Comparison of Insects, Birds, and Mammals

“…Indeed, a single nucleotide polymorphism in the OAS1b gene, namely rs34137742, that contains a C to T substitution in the second intron of the gene, is a risk factor for human West Nile encephalitis and paralysis from WNV infection (Bigham et al, 2011 ). OAS1 has been demonstrated to undergo positive selection in Old World primates (Fish and Boissinot, 2016 ), indicating a historic interaction between flaviviruses like WNV and host immunity (Daugherty and Malik, 2012 ). This pathway is conserved in birds and horses, as discussed in earlier sections.…”