Abstract

Viruses interact with the intracellular transport machinery to promote viral replication. Such host-virus interactions can drive host gene adaptation, leaving signatures of pathogen-driven evolution in host genomes. Here we leverage these genetic signatures to identify the dynein activating adaptor, ninein-like (NINL), as a critical component in the antiviral innate immune response and as a target of viral antagonism. Unique among genes en­­coding components of active dynein complexes, NINL has evolved under recurrent positive (diversifying) selection, particularly in its carboxy-terminal cargo binding region. Consistent with a role for NINL in host immunity, we demonstrate that NINL knockout cells exhibit an impaired response to interferon, resulting in increased permissiveness to viral replication. Moreover, we show that proteases encoded by diverse picornaviruses and coronaviruses cleave and disrupt NINL function in a host- and virus-specific manner. Our work reveals the importance of NINL in the antiviral response and the utility of using signatures of host-virus genetic conflicts to uncover new components of antiviral immunity and targets of viral antagonism.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.The NCBI nucleotide database (https://www.ncbi.nlm.nih.gov/nucleotide/) was used to collect sequences for human and non-human primate genes shown in Figure 1.Source Data files have been provided for Figures 2 through 7.RNA sequencing data used in Figure 3 have been deposited in GEO under accession code GSE206784.

The following data sets were generated

Article and author information

Author details

  1. Donte Alexander Stevens

    Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3732-9972
  2. Christopher Beierschmitt

    Department of Molecular Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0151-1091
  3. Swetha Mahesula

    Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    No competing interests declared.
  4. Miles R Corley

    Department of Molecular Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  5. John Salogiannis

    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, United States
    Competing interests
    No competing interests declared.
  6. Brian V Tsu

    Department of Molecular Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0268-8323
  7. Bryant Cao

    Department of Molecular Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  8. Andrew P Ryan

    Department of Molecular Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2630-9837
  9. Hiroyuki Hakozawki

    Nikon Imaging Center, University of California, San Diego, San Diego, United States
    Competing interests
    No competing interests declared.
  10. Samara L Reck-Peterson

    Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
    For correspondence
    sreckpeterson@ucsd.edu
    Competing interests
    Samara L Reck-Peterson, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1553-465X
  11. Matthew D Daugherty

    Department of Molecular Biology, University of California, San Diego, La Jolla, United States
    For correspondence
    mddaugherty@ucsd.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4879-9603

Funding

National Institute of General Medical Sciences (GM133633)

  • Matthew D Daugherty

National Institute of General Medical Sciences (GM141825)

  • Samara L Reck-Peterson

National Institute of General Medical Sciences (GM007240)

  • Donte Alexander Stevens
  • Christopher Beierschmitt
  • Brian V Tsu
  • Andrew P Ryan

Howard Hughes Medical Institute

  • Samara L Reck-Peterson

National Science Foundation (GRFP)

  • Donte Alexander Stevens
  • Christopher Beierschmitt

Howard Hughes Medical Institute (Gilliam Fellowship)

  • Donte Alexander Stevens

Pew Charitable Trusts (Biomedical Scholars Program)

  • Matthew D Daugherty

Burroughs Wellcome Fund (Investigators in the Pathogenesis of Infectious Diseases)

  • Matthew D Daugherty

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Sara Cherry, University of Pennsylvania, United States

Version history

  1. Received: July 4, 2022
  2. Preprint posted: July 11, 2022 (view preprint)
  3. Accepted: October 11, 2022
  4. Accepted Manuscript published: October 12, 2022 (version 1)
  5. Version of Record published: November 11, 2022 (version 2)

Copyright

© 2022, Stevens 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. Donte Alexander Stevens
  2. Christopher Beierschmitt
  3. Swetha Mahesula
  4. Miles R Corley
  5. John Salogiannis
  6. Brian V Tsu
  7. Bryant Cao
  8. Andrew P Ryan
  9. Hiroyuki Hakozawki
  10. Samara L Reck-Peterson
  11. Matthew D Daugherty
(2022)
Antiviral function and viral antagonism of the rapidly evolving dynein activating adapter NINL
eLife 11:e81606.
https://doi.org/10.7554/eLife.81606

Share this article

https://doi.org/10.7554/eLife.81606

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