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WDR77 inhibits prion-like aggregation of MAVS to limit antiviral innate immune response

Author

Listed:
  • Jiaxin Li

    (Chinese Academy of Sciences; University of Chinese Academy of Sciences)

  • Rui Zhang

    (Chinese Academy of Sciences; University of Chinese Academy of Sciences)

  • Changwan Wang

    (Chinese Academy of Sciences; University of Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Junyan Zhu

    (Chinese Academy of Sciences; University of Chinese Academy of Sciences)

  • Miao Ren

    (Chinese Academy of Sciences; University of Chinese Academy of Sciences)

  • Yingbo Jiang

    (Chinese Academy of Sciences; University of Chinese Academy of Sciences)

  • Xianteng Hou

    (Chinese Academy of Sciences; University of Chinese Academy of Sciences)

  • Yangting Du

    (Chinese Academy of Sciences; University of Chinese Academy of Sciences)

  • Qing Wu

    (Chinese Academy of Sciences; University of Chinese Academy of Sciences)

  • Shishi Qi

    (Chinese Academy of Sciences; University of Chinese Academy of Sciences)

  • Lin Li

    (National Institute of Biological Sciences)

  • She Chen

    (National Institute of Biological Sciences)

  • Hui Yang

    (Fudan University)

  • Fajian Hou

    (Chinese Academy of Sciences; University of Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

Abstract

RIG-I-MAVS signaling pathway plays a crucial role in defending against pathogen infection and maintaining immune balance. Upon detecting viral RNA, RIG-I triggers the formation of prion-like aggregates of the adaptor protein MAVS, which then activates the innate antiviral immune response. However, the mechanisms that regulate the aggregation of MAVS are not yet fully understood. Here, we identified WDR77 as a MAVS-associated protein, which negatively regulates MAVS aggregation. WDR77 binds to MAVS proline-rich region through its WD2-WD3-WD4 domain and inhibits the formation of prion-like filament of recombinant MAVS in vitro. In response to virus infection, WDR77 is recruited to MAVS to prevent the formation of its prion-like aggregates and thus downregulate RIG-I-MAVS signaling in cells. WDR77 deficiency significantly potentiates the induction of antiviral genes upon negative-strand RNA virus infections, and myeloid-specific Wdr77-deficient mice are more resistant to RNA virus infection. Our findings reveal that WDR77 acts as a negative regulator of the RIG-I-MAVS signaling pathway by inhibiting the prion-like aggregation of MAVS to prevent harmful inflammation.

Suggested Citation

  • Jiaxin Li & Rui Zhang & Changwan Wang & Junyan Zhu & Miao Ren & Yingbo Jiang & Xianteng Hou & Yangting Du & Qing Wu & Shishi Qi & Lin Li & She Chen & Hui Yang & Fajian Hou, 2023. "WDR77 inhibits prion-like aggregation of MAVS to limit antiviral innate immune response," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40567-5
    DOI: 10.1038/s41467-023-40567-5
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    References listed on IDEAS

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    1. Etienne Meylan & Joseph Curran & Kay Hofmann & Darius Moradpour & Marco Binder & Ralf Bartenschlager & Jürg Tschopp, 2005. "Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus," Nature, Nature, vol. 437(7062), pages 1167-1172, October.
    2. Xuemei Bai & Chao Sui & Feng Liu & Tian Chen & Lei Zhang & Yi Zheng & Bingyu Liu & Chengjiang Gao, 2022. "The protein arginine methyltransferase PRMT9 attenuates MAVS activation through arginine methylation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Yuheng Shi & Bofeng Yuan & Nan Qi & Wenting Zhu & Jingru Su & Xiaoyan Li & Peipei Qi & Dan Zhang & Fajian Hou, 2015. "An autoinhibitory mechanism modulates MAVS activity in antiviral innate immune response," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    4. Nan Qi & Yuheng Shi & Rui Zhang & Wenting Zhu & Bofeng Yuan & Xiaoyan Li & Changwan Wang & Xuewu Zhang & Fajian Hou, 2017. "Multiple truncated isoforms of MAVS prevent its spontaneous aggregation in antiviral innate immune signalling," Nature Communications, Nature, vol. 8(1), pages 1-16, August.
    5. Alys Peisley & Bin Wu & Hui Xu & Zhijian J. Chen & Sun Hur, 2014. "Structural basis for ubiquitin-mediated antiviral signal activation by RIG-I," Nature, Nature, vol. 509(7498), pages 110-114, May.
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