Oligoadenylate Synthetases 1 Enhances DNA Sensor Cgas Translation to Mediate Antiviral Activity

Abstract

Oligoadenylate synthetases (OAS) are a family of interferon (IFN)-stimulated genes known to inhibit viral replication through the enzymatic synthesis of 2'-5' oligoadenylates and activation of Ribonuclease L. However, this canonical mechanism does not explain the antiviral properties of enzymatically inactive OAS proteins. Here we describe an enzyme activity-independent function of OAS1 that restricts West Nile virus (WNV) growth. The human OAS1 P46 isoform, generated by alternative splicing of the G allele of rs10774671 SNP, upregulates translation of specific host mRNA including the DNA-sensor cGAS. Increased cGAS expression by OAS1 P46 augments the type I IFN response and inhibits WNV infection. A mouse Oas1 gene, Oas1b, also inhibits WNV growth through a similar mechanism. Specific residues in the RNA binding domains of P46 and Oas1b that regulate association of cGAS mRNA with OAS1, also control the antiviral activity. Our findings explain how some enzymatically inactive OAS1 proteins function as antiviral molecules.