State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, 200031, China.
Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
Nat Commun. 2023 Aug 10;14(1):4824. doi: 10.1038/s41467-023-40567-5.
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.
RIG-I-MAVS 信号通路在抵御病原体感染和维持免疫平衡方面发挥着关键作用。在检测到病毒 RNA 后，RIG-I 触发衔接蛋白 MAVS 的类朊病毒聚集物的形成，从而激活先天抗病毒免疫反应。然而，调节 MAVS 聚集的机制尚不完全清楚。在这里，我们鉴定出 WDR77 是一种与 MAVS 相关的蛋白，它负调控 MAVS 的聚集。WDR77 通过其 WD2-WD3-WD4 结构域与 MAVS 的富含脯氨酸的区域结合，并抑制重组 MAVS 的类朊病毒纤维在体外的形成。在病毒感染时，WDR77 被募集到 MAVS 以防止其类朊病毒聚集物的形成，从而下调细胞中的 RIG-I-MAVS 信号。在负链 RNA 病毒感染时，WDR77 缺失显著增强了抗病毒基因的诱导，并且髓样细胞特异性 Wdr77 缺陷小鼠对 RNA 病毒感染的抵抗力更强。我们的发现表明，WDR77 通过抑制 MAVS 的类朊病毒聚集来防止有害炎症，从而作为 RIG-I-MAVS 信号通路的负调控因子发挥作用。
