Antiviral function and viral antagonism of the rapidly evolving dynein activating adapter NINL
- University of California, San Diego, United States
- University of Vermont, United States
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.
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Antiviral function and viral antagonism of the rapidly evolving dynein activating adapter NINLNCBI Gene Expression Omnibus, GSE206784.
Article and author information
Author details
Donte Alexander Stevens
Christopher Beierschmitt
Samara L Reck-Peterson
Matthew D Daugherty
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.
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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Antiviral function and viral antagonism of the rapidly evolving dynein activating adapter NINL
eLife 11:e81606.
https://doi.org/10.7554/eLife.81606
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