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Summary Interferon-inducible human oligoadenylate synthetase-like (OASL) and its mouse ortholog, Oasl2 , enhance RNA-sensor RIG-I-mediated type I interferon (IFN) induction and inhibit RNA virus replication. Here, we show that OASL and Oasl2 have the opposite effect in the context of DNA virus infection. In Oasl2 −/− mice and OASL -deficient human cells, DNA viruses such as vaccinia, herpes simplex, and adenovirus induced increased IFN production, which resulted in reduced virus replication and pathology. Correspondingly, ectopic expression of OASL in human cells inhibited IFN induction through the cGAS-STING DNA-sensing pathway. cGAS was necessary for the reduced DNA virus replication observed in OASL -deficient cells. OASL directly and specifically bound to cGAS independently of double-stranded DNA, resulting in a non-competitive inhibition of the second messenger cyclic GMP-AMP production. Our findings define distinct mechanisms by which OASL differentially regulates host IFN responses during RNA and DNA virus infection and identify OASL as a negative-feedback regulator of cGAS. Graphical Abstract Highlights • Loss of human OASL and mouse Oasl2 inhibits DNA virus infection • OASL and Oasl2 inhibit cGAS-mediated IFN induction • OASL specifically binds to cGAS to inhibit cGAS enzyme activity • OASL binds to cGAS independently of double-stranded DNA The interferon (IFN)-stimulated gene OASL enhances RNA-sensor RIG-I-mediated IFN induction to inhibit RNA virus replication. In contrast, Ghosh et al. show that during DNA virus infection, OASL binds to the DNA sensor cGAS to inhibit IFN induction and enhance DNA virus replication. These findings highlight the distinct regulation of IFN induction by OASL during RNA and DNA virus infection. [ABSTRACT FROM AUTHOR]

In response to viral infection, how cells balance translational shutdown to limit viral replication and the induction of antiviral components like interferons (IFNs) is not well understood. Moreover, how distinct isoforms of IFN-induced oligoadenylate synthetase 1 (OAS1) contribute to this antiviral response also requires further elucidation. Here, we show that human, but not mouse, OAS1 inhibits SARS-CoV-2 replication through its canonical enzyme activity via RNase L. In contrast, both mouse and human OAS1 protect against West Nile virus infection by a mechanism distinct from canonical RNase L activation. OAS1 binds AU-rich elements (AREs) of specific mRNAs, including IFNβ. This binding leads to the sequestration of IFNβ mRNA to the endomembrane regions, resulting in prolonged half-life and continued translation. Thus, OAS1 is an ARE-binding protein with two mechanisms of antiviral activity: driving inhibition of translation but also a broader, non-canonical function of protecting IFN expression from translational shutdown. [Display omitted] • Human and mouse OAS1 protect against WNV through a non-canonical mechanism • OAS1 binds multiple cellular mRNAs through its unique endomembrane localization • OAS1 binds to the ARE region of IFN mRNA, which prolongs half-life and expression • Increased IFN expression by OAS1 leads to WNV inhibition via IFNAR signaling How cells induce the production of antiviral molecules while shutting down protein translation to limit viral replication remains unclear. Here, Harioudh et al. show a non-canonical function for the interferon-induced antiviral protein, OAS1, which sequesters and protects Ifnb mRNA from degradation to sustain innate antiviral protection against West Nile virus. [ABSTRACT FROM AUTHOR]