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

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 and Fajian Hou ()
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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
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

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40567-5

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