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The poxvirus F17 protein counteracts mitochondrially orchestrated antiviral responses

Author

Listed:
  • Nathan Meade

    (Northwestern University)

  • Helen K. Toreev

    (Northwestern University)

  • Ram P. Chakrabarty

    (Northwestern University)

  • Charles R. Hesser

    (Northwestern University)

  • Chorong Park

    (Northwestern University)

  • Navdeep S. Chandel

    (Northwestern University)

  • Derek Walsh

    (Northwestern University)

Abstract

Poxviruses are unusual DNA viruses that replicate in the cytoplasm. To do so, they encode approximately 100 immunomodulatory proteins that counteract cytosolic nucleic acid sensors such as cGAMP synthase (cGAS) along with several other antiviral response pathways. Yet most of these immunomodulators are expressed very early in infection while many are variable host range determinants, and significant gaps remain in our understanding of poxvirus sensing and evasion strategies. Here, we show that after infection is established, subsequent progression of the viral lifecycle is sensed through specific changes to mitochondria that coordinate distinct aspects of the antiviral response. Unlike other viruses that cause extensive mitochondrial damage, poxviruses sustain key mitochondrial functions including membrane potential and respiration while reducing reactive oxygen species that drive inflammation. However, poxvirus replication induces mitochondrial hyperfusion that independently controls the release of mitochondrial DNA (mtDNA) to prime nucleic acid sensors and enables an increase in glycolysis that is necessary to support interferon stimulated gene (ISG) production. To counter this, the poxvirus F17 protein localizes to mitochondria and dysregulates mTOR to simultaneously destabilize cGAS and block increases in glycolysis. Our findings reveal how the poxvirus F17 protein disarms specific mitochondrially orchestrated responses to later stages of poxvirus replication.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43635-y
    DOI: 10.1038/s41467-023-43635-y
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    1. A. Phillip West & William Khoury-Hanold & Matthew Staron & Michal C. Tal & Cristiana M. Pineda & Sabine M. Lang & Megan Bestwick & Brett A. Duguay & Nuno Raimundo & Donna A. MacDuff & Susan M. Kaech &, 2015. "Mitochondrial DNA stress primes the antiviral innate immune response," Nature, Nature, vol. 520(7548), pages 553-557, April.
    2. Inmaculada Martínez-Reyes & Luzivette Robles Cardona & Hyewon Kong & Karthik Vasan & Gregory S. McElroy & Marie Werner & Hermon Kihshen & Colleen R. Reczek & Samuel E. Weinberg & Peng Gao & Elizabeth , 2020. "Mitochondrial ubiquinol oxidation is necessary for tumour growth," Nature, Nature, vol. 585(7824), pages 288-292, September.
    3. Dean J. Procter & Colleen Furey & Arturo G. Garza-Gongora & Steven T. Kosak & Derek Walsh, 2020. "Cytoplasmic control of intranuclear polarity by human cytomegalovirus," Nature, Nature, vol. 587(7832), pages 109-114, November.
    4. Miyu Moriyama & Takumi Koshiba & Takeshi Ichinohe, 2019. "Influenza A virus M2 protein triggers mitochondrial DNA-mediated antiviral immune responses," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    5. 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.
    6. 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.
    7. 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.
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