%0 Journal Article
%T Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling
%A Fanhua Wei
%A George Fu Gao
%A Honglei Sun
%A Jinhua Liu
%A Juan Pu
%A Mingyang Wang
%A Qi Tong
%A Xiaojing Ma
%A Yipeng Sun
%A Yuhai Bi
%A Zhimin Jiang
%J -
%D 2019
%R 10.1371/journal.ppat.1008062
%X 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-¦ĘB and IRF3 signaling. Furthermore, we showed that PGRN directly interacted with NF-¦ĘB 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
%K Influenza viruses
%K Transcription factors
%K Antibodies
%K Influenza
%K Transfection
%K Small interfering RNAs
%K Macrophages
%K Ubiquitination
%U https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008062