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

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


    PLoS Pathog. 2019 Oct 4;15(10):e1008062. doi: 10.1371/journal.ppat.1008062. [Epub ahead of print] Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling.

    Wei F1,2, Jiang Z1, Sun H1, Pu J1, Sun Y1, Wang M1, Tong Q1, Bi Y3, Ma X4,5, Gao GF3, Liu J1.
    Author information

    1 Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China. 2 College of Agriculture, Ningxia University, Yinchuan, China. 3 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Institute of Microbiology, Center for Influenza Research and Early-Warning (CASCIRE), Chinese Academy of Sciences, Beijing, China. 4 State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. 5 Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America.

    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.


    PMID: 31585000 DOI: 10.1371/journal.ppat.1008062
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