1. Immunology and Inflammation
  2. Microbiology and Infectious Disease

Antiviral function and viral antagonism of the rapidly evolving dynein activating adapter NINL

  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  Is a corresponding author
  11. Matthew D Daugherty  Is a corresponding author
  1. University of California, San Diego, United States
  2. University of Vermont, United States
https://doi.org/10.7554/eLife.81606
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.

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.

Metrics

  • 1,482
    views
  • 238
    downloads
  • 13
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Categories and tags

Research organisms

Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease

    Soluble immune mediators orchestrate protective in vitro granulomatous responses across Mycobacterium tuberculosis complex lineages

    Ainhoa Arbués, Sarah Schmidiger ... Damien Portevin
    Research Article

    The members of the Mycobacterium tuberculosis complex (MTBC) causing human tuberculosis comprise 10 phylogenetic lineages that differ in their geographical distribution. The human consequences of this phylogenetic diversity remain poorly understood. Here, we assessed the phenotypic properties at the host-pathogen interface of 14 clinical strains representing five major MTBC lineages. Using a human in vitro granuloma model combined with bacterial load assessment, microscopy, flow cytometry, and multiplexed-bead arrays, we observed considerable intra-lineage diversity. Yet, modern lineages were overall associated with increased growth rate and more pronounced granulomatous responses. MTBC lineages exhibited distinct propensities to accumulate triglyceride lipid droplets—a phenotype associated with dormancy—that was particularly pronounced in lineage 2 and reduced in lineage 3 strains. The most favorable granuloma responses were associated with strong CD4 and CD8 T cell activation as well as inflammatory responses mediated by CXCL9, granzyme B, and TNF. Both of which showed consistent negative correlation with bacterial proliferation across genetically distant MTBC strains of different lineages. Taken together, our data indicate that different virulence strategies and protective immune traits associate with MTBC genetic diversity at lineage and strain level.

    1. Immunology and Inflammation

    Inflammasomes: A tale of two caspases

    Denise M Monack
    Insight

    Macrophages control intracellular pathogens like Salmonella by using two caspase enzymes at different times during infection.

    1. Immunology and Inflammation
    2. Medicine

    Deciphering the preeclampsia-specific immune microenvironment and the role of pro-inflammatory macrophages at the maternal–fetal interface

    Haiyi Fei, Xiaowen Lu ... Lingling Jiang
    Research Article

    Preeclampsia (PE), a major cause of maternal and perinatal mortality with highly heterogeneous causes and symptoms, is usually complicated by gestational diabetes mellitus (GDM). However, a comprehensive understanding of the immune microenvironment in the placenta of PE and the differences between PE and GDM is still lacking. In this study, cytometry by time of flight indicated that the frequencies of memory-like Th17 cells (CD45RA−CCR7+IL-17A+CD4+), memory-like CD8+ T cells (CD38+CXCR3−CCR7+Helios−CD127−CD8+) and pro-inflam Macs (CD206−CD163−CD38midCD107alowCD86midHLA-DRmidCD14+) were increased, while the frequencies of anti-inflam Macs (CD206+CD163−CD86midCD33+HLA-DR+CD14+) and granulocyte myeloid-derived suppressor cells (gMDSCs, CD11b+CD15hiHLA-DRlow) were decreased in the placenta of PE compared with that of normal pregnancy (NP), but not in that of GDM or GDM&PE. The pro-inflam Macs were positively correlated with memory-like Th17 cells and memory-like CD8+ T cells but negatively correlated with gMDSCs. Single-cell RNA sequencing revealed that transferring the F4/80+CD206− pro-inflam Macs with a Folr2+Ccl7+Ccl8+C1qa+C1qb+C1qc+ phenotype from the uterus of PE mice to normal pregnant mice induced the production of memory-like IL-17a+Rora+Il1r1+TNF+Cxcr6+S100a4+CD44+ Th17 cells via IGF1–IGF1R, which contributed to the development and recurrence of PE. Pro-inflam Macs also induced the production of memory-like CD8+ T cells but inhibited the production of Ly6g+S100a8+S100a9+Retnlg+Wfdc21+ gMDSCs at the maternal–fetal interface, leading to PE-like symptoms in mice. In conclusion, this study revealed the PE-specific immune cell network, which was regulated by pro-inflam Macs, providing new ideas about the pathogenesis of PE.