TY - JOUR
T1 - Endomembrane targeting of human OAS1 p46 augments antiviral activity
AU - Soveg, Frank W.
AU - Schwerk, Johannes
AU - Gokhale, Nandan S.
AU - Cerosaletti, Karen
AU - Smith, Julian R.
AU - Pairo-Castineira, Erola
AU - Kell, Alison M.
AU - Forero, Adriana
AU - Zaver, Shivam A.
AU - Esser-Nobis, Katharina
AU - Roby, Justin A.
AU - Hsiang, Tien Ying
AU - Ozarkar, Snehal
AU - Clingan, Jonathan M.
AU - McAnarney, Eileen T.
AU - Stone, Amy E.L.
AU - Malhotra, Uma
AU - Speake, Cate
AU - Perez, Joseph
AU - Balu, Chiraag
AU - Allenspach, Eric J.
AU - Hyde, Jennifer L.
AU - Menachery, Vineet D.
AU - Sarkar, Saumendra N.
AU - Woodward, Joshua J.
AU - Stetson, Daniel B.
AU - Baillie, John Kenneth
AU - Buckner, Jane H.
AU - Gale, Michael
AU - Savan, Ram
N1 - Publisher Copyright:
© Soveg et al.
PY - 2021
Y1 - 2021
N2 - 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 coopted 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.
AB - 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 coopted 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.
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U2 - 10.7554/ELIFE.71047
DO - 10.7554/ELIFE.71047
M3 - Article
C2 - 34342578
AN - SCOPUS:85112365093
SN - 2050-084X
VL - 10
JO - eLife
JF - eLife
M1 - e71047
ER -