Endomembrane targeting of human OAS1 p46 augments antiviral activity

Frank W Soveg, Johannes Schwerk, Nandan S Gokhale, Karen Cerosaletti, Julian R Smith, Erola Pairo-Castineira, Alison M Kell, Adriana Forero, Shivam A Zaver, Katharina Esser-Nobis, Justin A Roby, Tien-Ying Hsiang, Snehal Ozarkar, Jonathan M Clingan, Eileen T McAnarney, Amy El Stone, Uma Malhotra, Cate Speake, Joseph Perez, Chiraag BaluEric J Allenspach, Jennifer L Hyde, Vineet D Menachery, Saumendra N Sarkar, Joshua J Woodward, Daniel B Stetson, John Kenneth Baillie, Jane H Buckner, Michael Gale, Ram Savan

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from cellular innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flaviviruses, picornaviruses, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform correlates with protection from severe COVID-19. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests that early control of SARS-CoV-2 replication through OAS1 p46 is an important determinant of COVID-19 severity.

Original languageEnglish
Publication statusPublished - 3 Aug 2021


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