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Vaccinia E5 is a major inhibitor of the DNA sensor cGAS

Author

Listed:
  • Ning Yang

    (Memorial Sloan Kettering Cancer Center)

  • Yi Wang

    (Memorial Sloan Kettering Cancer Center)

  • Peihong Dai

    (Memorial Sloan Kettering Cancer Center)

  • Tuo Li

    (University of Texas Southwestern Medical Center)

  • Christian Zierhut

    (The Rockefeller University
    The Institute of Cancer Research)

  • Adrian Tan

    (Weill Cornell Medical College)

  • Tuo Zhang

    (Weill Cornell Medical College)

  • Jenny Zhaoying Xiang

    (Weill Cornell Medical College)

  • Alban Ordureau

    (Memorial Sloan Kettering Cancer Center)

  • Hironori Funabiki

    (The Rockefeller University)

  • Zhijian Chen

    (University of Texas Southwestern Medical Center)

  • Liang Deng

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center
    Weill Cornell Medical College)

Abstract

The DNA sensor cyclic GMP-AMP synthase (cGAS) is critical in host antiviral immunity. Vaccinia virus (VACV) is a large cytoplasmic DNA virus that belongs to the poxvirus family. How vaccinia virus antagonizes the cGAS-mediated cytosolic DNA-sensing pathway is not well understood. In this study, we screened 80 vaccinia genes to identify potential viral inhibitors of the cGAS/Stimulator of interferon gene (STING) pathway. We discovered that vaccinia E5 is a virulence factor and a major inhibitor of cGAS. E5 is responsible for abolishing cGAMP production during vaccinia virus (Western Reserve strain) infection of dendritic cells. E5 localizes to the cytoplasm and nucleus of infected cells. Cytosolic E5 triggers ubiquitination of cGAS and proteasome-dependent degradation via interacting with cGAS. Deleting the E5R gene from the Modified vaccinia virus Ankara (MVA) genome strongly induces type I IFN production by dendritic cells (DCs) and promotes DC maturation, and thereby improves antigen-specific T cell responses.

Suggested Citation

  • Ning Yang & Yi Wang & Peihong Dai & Tuo Li & Christian Zierhut & Adrian Tan & Tuo Zhang & Jenny Zhaoying Xiang & Alban Ordureau & Hironori Funabiki & Zhijian Chen & Liang Deng, 2023. "Vaccinia E5 is a major inhibitor of the DNA sensor cGAS," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38514-5
    DOI: 10.1038/s41467-023-38514-5
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    References listed on IDEAS

    as
    1. James B. Eaglesham & Youdong Pan & Thomas S. Kupper & Philip J. Kranzusch, 2019. "Viral and metazoan poxins are cGAMP-specific nucleases that restrict cGAS–STING signalling," Nature, Nature, vol. 566(7743), pages 259-263, February.
    2. Ning Yang & Joseph M. Luna & Peihong Dai & Yi Wang & Charles M. Rice & Liang Deng, 2022. "Lung type II alveolar epithelial cells collaborate with CCR2+ inflammatory monocytes in host defense against poxvirus infection," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. James B. Eaglesham & Youdong Pan & Thomas S. Kupper & Philip J. Kranzusch, 2019. "Publisher Correction: Viral and metazoan poxins are cGAMP-specific nucleases that restrict cGAS–STING signalling," Nature, Nature, vol. 569(7758), pages 12-12, May.
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    Cited by:

    1. Nathan Meade & Helen K. Toreev & Ram P. Chakrabarty & Charles R. Hesser & Chorong Park & Navdeep S. Chandel & Derek Walsh, 2023. "The poxvirus F17 protein counteracts mitochondrially orchestrated antiviral responses," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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