1. Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling.
- Author
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Wei, Fanhua, Jiang, Zhimin, Sun, Honglei, Pu, Juan, Sun, Yipeng, Wang, Mingyang, Tong, Qi, Bi, Yuhai, Ma, Xiaojing, Gao, George Fu, and Liu, Jinhua
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TYPE I interferons , *INFLUENZA A virus , *VIRUS diseases , *IMMUNE response , *SMALL interfering RNA , *DOWNREGULATION - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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