Oligoadenylate Synthetase 1 enhances DNA sensor cGAS translation to mediate WNV antiviral activity

Abstract

Abstract Interferons inhibit virus replication through the expression of interferon stimulated genes (ISGs). We have found that a specific isoform of one such ISG, Oligoadenylate Synthetase 1 (OAS1) limits host susceptibility to West Nile Virus (WNV) infection through a non-canonical mechanism. This OAS1 isoform (OAS1 P46) in humans is generated due to an alternative splice acceptor site at the C-terminus of OAS1 gene. The SNP rs10774671 at this site has been associated with disease severity to WNV. We show that human OAS1-KO cells have lower basal levels of cGAS protein and can be rescued by OAS1 P46 independent of its enzyme activity. Additionally, through RNA-seq, SILAC, polysome profiling and radiolabeling experiments, we show that OAS1 does not regulate mRNA transcription but instead enhances protein translation of a select set of mRNAs, thereby increasing the steady state and induced levels of specific proteins with antiviral properties. Inducible expression of OAS1 P46 in cGAS-KO cells does not suppress WNV replication, suggesting that the antiviral activity of OAS1 is mediated through cGAS. We also have established functional equivalence between OAS1 P46 and a mouse ortholog, Oas1b (no enzyme activity), which similarly affects WNV susceptibility. Oas1b inhibits WNV infection and pathogenesis in vivo and inhibits WNV infection in vitro in cGAS-dependent manner. Through RNA-protein crosslinking experiments we have identified target mRNAs that bind to OAS1 and have demonstrated increased sensitivity of WNV in Oas1b RNA binding mutants. Our findings suggest a novel mechanism of OAS1 in which it binds to target mRNAs, enhances the translation of these RNAs and limits virus infection.