Announcement

Collapse
No announcement yet.

J Virol . The Nucleoprotein of H7N9 Influenza Virus Positively Regulates TRAF3-Mediated Innate Signaling and Attenuates Viral Virulence in Mice

Collapse
X
 
  • Filter
  • Time
  • Show
Clear All
new posts

  • J Virol . The Nucleoprotein of H7N9 Influenza Virus Positively Regulates TRAF3-Mediated Innate Signaling and Attenuates Viral Virulence in Mice


    J Virol


    . 2020 Oct 7;JVI.01640-20.
    doi: 10.1128/JVI.01640-20. Online ahead of print.
    The Nucleoprotein of H7N9 Influenza Virus Positively Regulates TRAF3-Mediated Innate Signaling and Attenuates Viral Virulence in Mice


    Yanli Wei 1 , Yan Zeng 1 , Xuegang Zhang 1 , Shuai Xu 1 , Zhengxiang Wang 1 , Yingying Du 1 , Bo Zhang 1 2 , Cao-Qi Lei 3 , Qiyun Zhu 4



    Affiliations

    Abstract

    H7N9 influenza A virus (IAV) is an emerged contagious pathogen that may cause severe human infections, even death. Understanding the precise cross-talk between virus and host is vital for the development of effective vaccines and therapeutics. In the present study, we identified the nucleoprotein (NP) of H7N9 IAV as a positive regulator of RIG-I like receptor (RLR)-mediated signaling. Based on a loss-of-function strategy, we replaced H1N1 (mouse-adapted PR8 strain) NP with H7N9 NP, by using reverse genetics, and found that the replication and pathogenicity of rPR8-H7N9NP were significantly attenuated in cells and mice. Biochemical and cellular analyses revealed that H7N9 NP specifically interacts with tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) after viral infection. Subsequently, we identified a PxxQxS motif in the H7N9 NP protein that may be a determinant for the NP and TRAF3 interaction. Furthermore, H7N9 NP stabilized TRAF3 expression via competitively binding to TRAF3 with cellular inhibitor of apoptosis 2 (cIAP2), leading to the inhibition of the Lys48-linked polyubiquitination and degradation of TRAF3. Taken together, these data uncover a novel mechanism by which the NP protein of H7N9 IAV positively regulates TRAF3-mediated type I interferon signaling. Our findings provide insights into virus and host survival strategies that involve a specific viral protein that modulates an appropriate immune response in hosts.IMPORTANCE The NS1, PB2, PA-X, and PB1-F2 proteins of influenza A virus (IAV) are known to employ various strategies to counteract and evade host defenses. However, the viral components responsible for the activation of innate immune signaling remain elusive. In this study, we demonstrate for the first time that the NP protein of H7N9 IAV specifically associates with and stabilizes the important adaptor molecule TRAF3, which potentiates RLR-mediated type I interferon induction. Moreover, we reveal that this H7N9 protein prevents the interaction between TRAF3 and cIAP2 that mediates Lys48-linked polyubiquitination of TRAF3 for degradation. The current study reveals a novel mechanism by which H7N9 NP upregulates TRAF3-mediated type I interferon production, leading to attenuation of viral replication and pathogenicity in cells and mice. Our finding provides a possible explanation for virus and host commensalism via viral manipulation of the host immune system.


Working...
X