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

Autoři: Fanhua Wei aff001;  Zhimin Jiang aff001;  Honglei Sun aff001;  Juan Pu aff001;  Yipeng Sun aff001;  Mingyang Wang aff001;  Qi Tong aff001;  Yuhai Bi aff003;  Xiaojing Ma aff004;  George Fu Gao aff003;  Jinhua Liu aff001
Působiště autorů: 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 aff001;  College of Agriculture, Ningxia University, Yinchuan, China aff002;  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 Scien aff003;  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 aff004;  Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America aff005
Vyšlo v časopise: Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling. PLoS Pathog 15(10): e32767. doi:10.1371/journal.ppat.1008062
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008062


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.

Klíčová slova:

Antibodies – Influenza – Influenza viruses – Macrophages – Small interfering RNAs – Transfection – Ubiquitination – H5N1


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