Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I

Cell Host Microbe. 2009 May 8;5(5):439-49. doi: 10.1016/j.chom.2009.04.006.

Abstract

The ubiquitin ligase TRIM25 mediates Lysine 63-linked ubiquitination of the N-terminal CARD domains of the viral RNA sensor RIG-I to facilitate type I interferon (IFN) production and antiviral immunity. Here, we report that the influenza A virus nonstructural protein 1 (NS1) specifically inhibits TRIM25-mediated RIG-I CARD ubiquitination, thereby suppressing RIG-I signal transduction. A novel domain in NS1 comprising E96/E97 residues mediates its interaction with the coiled-coil domain of TRIM25, thus blocking TRIM25 multimerization and RIG-I CARD domain ubiquitination. Furthermore, a recombinant influenza A virus expressing an E96A/E97A NS1 mutant is defective in blocking TRIM25-mediated antiviral IFN response and loses virulence in mice. Our findings reveal a mechanism by which influenza virus inhibits host IFN response and also emphasize the vital role of TRIM25 in modulating antiviral defenses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • Female
  • Host-Pathogen Interactions*
  • Humans
  • Influenza A virus / chemistry
  • Influenza A virus / genetics
  • Influenza A virus / metabolism*
  • Influenza, Human / immunology
  • Influenza, Human / metabolism*
  • Influenza, Human / virology
  • Interferon Type I / immunology
  • Mice
  • Mice, Inbred BALB C
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Transport
  • Signal Transduction
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism*

Substances

  • INS1 protein, influenza virus
  • Interferon Type I
  • Transcription Factors
  • Tripartite Motif Proteins
  • Viral Nonstructural Proteins
  • TRIM25 protein, human
  • Ubiquitin-Protein Ligases
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases