Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling

作者：Fanhua Wei, Zhimin Jiang, Honglei Sun, Juan Pu, Yipeng Sun, Mingyang Wang, Qi Tong, Yuhai Bi, Xiaojing Ma, George F. Gao, Jinhua Liu · 发表于：PLoS Pathogens · 年份：2019 · DOI：10.1371/journal.ppat.1008062 · 被引用次数：40 · 研究领域：interferon and immune responses、Immune Response and Inflammation、Immune cells in cancer

Type I interferons (IFNs) play a critical role in host defense against influenza virus infection, and the mechanism of influenza virus to evade type I IFNs responses remains to be fully understood. Here, we found that progranulin (PGRN) was significantly increased both in vitro and in vivo during influenza virus infection. Using a PGRN knockdown assay and PGRN-deficient mice model, we demonstrated that influenza virus-inducing PGRN negatively regulated type I IFNs production by inhibiting the activation of NF-κB and IRF3 signaling. Furthermore, we showed that PGRN directly interacted with NF-κB essential modulator (NEMO) via its Grn CDE domains. We also verified that PGRN recruited A20 to deubiquitinate K63-linked polyubiquitin chains on NEMO at K264. In addition, we found that macrophage played a major source of PGRN during influenza virus infection, and PGRN neutralizing antibodies could protect against influenza virus-induced lethality in mice. Our data identify a PGRN-mediated IFN evasion pathway exploited by influenza virus with implication in antiviral applications. These findings also provide insights into the functions and crosstalk of PGRN in innate immunity.