Influenza virus NS1 interacts with 14-3-3ε to antagonize the production of RIG-I-mediated type I interferons

Virology. 2022 Sep;574:47-56. doi: 10.1016/j.virol.2022.07.002. Epub 2022 Jul 20.


For influenza A viruses (IAVs), non-structural protein 1 (NS1) protein was recognized to be the key factor to enhance virulence by antagonizing host innate anti-viral responses. However, for the pathways allowing NS1 to regulate the type I interferon (IFN) response, the identification of the substrates was still incomplete. Here a recombinant IAV encoding a NS1 containing an affinity tag (NS1-Strep) was generated to capture the NS1-interactome in the lungs of infected mice. Several scaffold proteins of the 14-3-3 family were distinguished as the most potent candidates. Based on the conserved motif RxxTxxT of NS1, the interaction between NS1 and 14-3-3ε was enabled, which competed for the binding of RIG-I to 14-3-3ε and prevented RIG-I translocation to the adaptor MAVS, consequently inhibiting IFN-β expression. A recombinant mutant IAV deficient in 14-3-3ε binding elicited a markable innate immune responses and showed impaired growth kinetics.

Keywords: 14-3-3 proteins; Influenza virus; NS1 protein; RIG-I translocation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / metabolism
  • Humans
  • Immunologic Factors / metabolism
  • Influenza A virus* / genetics
  • Influenza A virus* / metabolism
  • Influenza, Human*
  • Interferon Type I*
  • Interferon-beta / metabolism
  • Interferons / metabolism
  • Mice
  • Viral Nonstructural Proteins / metabolism


  • Immunologic Factors
  • Interferon Type I
  • Viral Nonstructural Proteins
  • Interferon-beta
  • Interferons
  • DEAD Box Protein 58