1. Microbiology and Infectious Disease
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Rotavirus VP3 targets MAVS for degradation to inhibit type III interferon expression in intestinal epithelial cells

  1. Siyuan Ding  Is a corresponding author
  2. Shu Zhu
  3. Lili Ren
  4. Ningguo Feng
  5. Yanhua Song
  6. Xiaomei Ge
  7. Bin Li
  8. Richard A Flavell
  9. Harry B Greenberg  Is a corresponding author
  1. Stanford University, United States
  2. University of Science and Technology of China, China
  3. Jiangsu Academy of Agricultural Sciences, China
  4. Yale University, United States
Research Article
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Cite this article as: eLife 2018;7:e39494 doi: 10.7554/eLife.39494

Abstract

Rotaviruses (RVs), a leading cause of severe diarrhea in young children1 and many mammalian species, have evolved multiple strategies to counteract the host innate immunity, specifically interferon (IFN) signaling through RV non-structural protein 1 (NSP1)2. However, whether RV structural components also subvert antiviral response remains under-studied. Here, we found that MAVS, critical for the host RNA sensing pathway upstream of IFN induction3, is degraded by the RV RNA methyl- and guanylyl-transferase (VP3) in a host-range-restricted manner. Mechanistically, VP3 localizes to the mitochondria and mediates the phosphorylation of a previously unidentified SPLTSS motif within the MAVS proline-rich region, leading to its proteasomal degradation and blockade of IFN-λ production in RV-infected intestinal epithelial cells. Importantly, VP3 inhibition of MAVS activity contributes to enhanced RV replication and to viral pathogenesis in vivo. Collectively, our findings establish RV VP3 as a viral antagonist of MAVS function in mammals and uncover a novel pathogen-mediated inhibitory mechanism of MAVS signaling.

Data availability

The data that support the findings of this study are available in the main text, main figures, supplementary figures or attached as Supplementary Tables 1 and 2. Additional information is available in the format of Source Data.

Article and author information

Author details

  1. Siyuan Ding

    Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, United States
    For correspondence
    syding@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Shu Zhu

    Institute of Immunology, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Lili Ren

    Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ningguo Feng

    Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yanhua Song

    Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Xiaomei Ge

    Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Bin Li

    Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Richard A Flavell

    Department of Immunobiology, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4461-0778
  9. Harry B Greenberg

    Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, United States
    For correspondence
    hbgreen@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2128-9080

Funding

National Institute of Allergy and Infectious Diseases (R01 AI125249)

  • Harry B Greenberg

National Institute of Allergy and Infectious Diseases (U19 AI116484)

  • Harry B Greenberg

Thrasher Research Fund (Early Career Award)

  • Siyuan Ding

National Natural Science Foundation of China (81788104)

  • Shu Zhu

Howard Hughes Medical Institute

  • Richard A Flavell

National Institute of Allergy and Infectious Diseases (K99 AI135031)

  • Siyuan Ding

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

Ethics

Animal experimentation: Age and sex-matched were used in this study. Mice were specific pathogen-free, maintained under a strict 12 hour light cycle, and given a regular chow diet ad libitum. All protocols used in this study were compliant with the Veterinary Medical Unit of Palo Alto VA Health Care System (PAVAHCS) and approved by the IACUC committee.

Reviewing Editor

  1. David M Knipe, Harvard Medical School, United States

Publication history

  1. Received: June 23, 2018
  2. Accepted: November 16, 2018
  3. Accepted Manuscript published: November 21, 2018 (version 1)
  4. Version of Record published: December 11, 2018 (version 2)

Copyright

© 2018, Ding 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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