Endomembrane targeting of human OAS1 p46 augments antiviral activity

  1. Frank W Soveg
  2. Johannes Schwerk
  3. Nandan S Gokhale
  4. Karen Cerosaletti
  5. Julian R Smith
  6. Erola Pairo-Castineira
  7. Alison M Kell
  8. Adriana Forero
  9. Shivam A Zaver
  10. Katharina Esser-Nobis
  11. Justin Roby
  12. Tien-Ying Hsiang
  13. Snehal Ozarkar
  14. Jonathan M Clingan
  15. Eileen T McAnarney
  16. Amy E L Stone
  17. Uma Malhotra
  18. Cate Speake
  19. Joseph Perez
  20. Chiraag Balu
  21. Eric J Allenspach
  22. Jennifer L Hyde
  23. Vineet D Menachery
  24. Saumendra N Sarkar
  25. Joshua J Woodward
  26. Daniel B Stetson
  27. John Kenneth Baillie
  28. Jane H Buckner
  29. Michael Gale Jr
  30. Ram Savan  Is a corresponding author
  1. The University of Washington, United States
  2. Benaroya Research Institute, United States
  3. University of Edinburgh, United Kingdom
  4. The University of New Mexico, United States
  5. The Ohio State University, United States
  6. University of Washington, United States
  7. Charles Sturt University, United States
  8. The University of Washingon, United States
  9. The University of Texas, Galveston, United States
  10. Touro University Nevada, United States
  11. Benaroya Research Institute at Virginia Mason, United States
  12. The University of Pittsburgh, United States
  13. University of Texas Medical Branch Galveston, United States
  14. University of Pittsburgh, United States
  15. 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

  1. Frank W Soveg

    The University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Johannes Schwerk

    The University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5964-7162
  3. Nandan S Gokhale

    The University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Karen Cerosaletti

    Benaroya Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7403-6239
  5. Julian R Smith

    The University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Erola Pairo-Castineira

    Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Alison M Kell

    The University of New Mexico, Albuquerque, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Adriana Forero

    The Ohio State University, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2698-658X
  9. Shivam A Zaver

    Department of Microbiology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Katharina Esser-Nobis

    The University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9027-0391
  11. Justin Roby

    Charles Sturt University, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Tien-Ying Hsiang

    The University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Snehal Ozarkar

    The University of Washingon, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Jonathan M Clingan

    The University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4729-0247
  15. Eileen T McAnarney

    The University of Texas, Galveston, Galveston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2337-2889
  16. Amy E L Stone

    Basic Sciences, Touro University Nevada, Henderson, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9140-6510
  17. Uma Malhotra

    The University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Cate Speake

    Benaroya Research Institute at Virginia Mason, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1480-4272
  19. Joseph Perez

    The University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Chiraag Balu

    The University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Eric J Allenspach

    Pediatrics, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7346-5835
  22. Jennifer L Hyde

    The University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8062-1672
  23. Vineet D Menachery

    Microbiology and Immunology, University of Texas Medical Branch Galveston, Galveston, United States
    Competing interests
    The authors declare that no competing interests exist.
  24. Saumendra N Sarkar

    University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2850-6121
  25. Joshua J Woodward

    Department of Microbiology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4630-403X
  26. Daniel B Stetson

    Department of Immunology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5936-1113
  27. John Kenneth Baillie

    Genetics and Genomics, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5258-793X
  28. Jane H Buckner

    Benaroya Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  29. Michael Gale Jr

    Department of Immunology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  30. Ram Savan

    Department of Immunology, University of Washington, Seattle, United States
    For correspondence
    savanram@uw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3087-1355

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.

Reviewing Editor

  1. Jos W Van der Meer, Radboud University Medical Centre, Netherlands

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).

Version history

  1. Preprint posted: April 22, 2021 (view preprint)
  2. Received: June 8, 2021
  3. Accepted: June 11, 2021
  4. Accepted Manuscript published: August 3, 2021 (version 1)
  5. 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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  1. Frank W Soveg
  2. Johannes Schwerk
  3. Nandan S Gokhale
  4. Karen Cerosaletti
  5. Julian R Smith
  6. Erola Pairo-Castineira
  7. Alison M Kell
  8. Adriana Forero
  9. Shivam A Zaver
  10. Katharina Esser-Nobis
  11. Justin Roby
  12. Tien-Ying Hsiang
  13. Snehal Ozarkar
  14. Jonathan M Clingan
  15. Eileen T McAnarney
  16. Amy E L Stone
  17. Uma Malhotra
  18. Cate Speake
  19. Joseph Perez
  20. Chiraag Balu
  21. Eric J Allenspach
  22. Jennifer L Hyde
  23. Vineet D Menachery
  24. Saumendra N Sarkar
  25. Joshua J Woodward
  26. Daniel B Stetson
  27. John Kenneth Baillie
  28. Jane H Buckner
  29. Michael Gale Jr
  30. Ram Savan
(2021)
Endomembrane targeting of human OAS1 p46 augments antiviral activity
eLife 10:e71047.
https://doi.org/10.7554/eLife.71047

Share this article

https://doi.org/10.7554/eLife.71047

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