Endomembrane targeting of human OAS1 p46 augments antiviral activity
- The University of Washington, United States
- Benaroya Research Institute, United States
- University of Edinburgh, United Kingdom
- The University of New Mexico, United States
- The Ohio State University, United States
- University of Washington, United States
- Charles Sturt University, United States
- The University of Washingon, United States
- The University of Texas, Galveston, United States
- Touro University Nevada, United States
- Benaroya Research Institute at Virginia Mason, United States
- The University of Pittsburgh, United States
- University of Texas Medical Branch Galveston, United States
- University of Pittsburgh, United States
- Roslin Institute, University of Edinburgh, United Kingdom
Abstract
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.
Data availability
All data generated during this study are provided in the manuscript, supporting files, and source data files.Raw PLINK results for the association analysis of local subjects are provided in Supplementary File 5; association data for the GenOMICC replication cohort is available as described in the primary publication (Pairo-Castineira et al., 2020).Additional data on our local COVID-19 cohort is available upon request (KCerosaletti@benaroyaresearch.org). This is being done to protect the privacy of the subjects in this study as the data were obtained from samples recovered from the hospital clinical laboratory with IRB approval but without written consent. For commercial entities, availability of these data will be assessed on a case-by-case basis in conjunction with the Benaroya Research Institute business development office.
Article and author information
Author details
Katharina Esser-Nobis
Jonathan M Clingan
Eileen T McAnarney
Saumendra N Sarkar
John Kenneth Baillie
Funding
National Institutes of Health (AI145974,AI108765,AI135437)
- Ram Savan
National Institutes of Health (AI104002,AI118916,AI145296,AI127463,AI100625)
- Frank W Soveg
National Institutes of Health (AI106677,GM007270,AI140530)
- Frank W Soveg
National Institutes of Health (T32 HL007312)
- Adriana Forero
Office of the Director of the National Institutes of Health (S10OD026741)
- Ram Savan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: A cohort of 99 healthy control subjects matched for ancestry (self-reported) was assembled from participants in the 1310 healthy control registry at Benaroya Research Institute. Both studies were approved by the Institutional Review Board at Benaroya Research Institute (IRB20-036 and IRB07109respectively).
Reviewing Editor
- Jos W Van der Meer, Radboud University Medical Centre, Netherlands
Version history
- Preprint posted: April 22, 2021 (view preprint)
- Received: June 8, 2021
- Accepted: June 11, 2021
- Accepted Manuscript published: August 3, 2021 (version 1)
- Version of Record published: August 11, 2021 (version 2)
Copyright
© 2021, Soveg et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Endomembrane targeting of human OAS1 p46 augments antiviral activity
eLife 10:e71047.
https://doi.org/10.7554/eLife.71047
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