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

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.

Pubmed ID: 19454348

Authors

  • Gack MU
  • Albrecht RA
  • Urano T
  • Inn KS
  • Huang IC
  • Carnero E
  • Farzan M
  • Inoue S
  • Jung JU
  • GarcĂ­a-Sastre A

Journal

Cell host & microbe

Publication Data

May 8, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: CA082057
  • Agency: NCI NIH HHS, Id: CA115284
  • Agency: NCI NIH HHS, Id: CA31363
  • Agency: NIDCR NIH HHS, Id: DE019085
  • Agency: NINDS NIH HHS, Id: HHNSN266200700010C
  • Agency: PHS HHS, Id: HHSN266200700010C
  • Agency: NIAID NIH HHS, Id: R01 AI046954
  • Agency: NIAID NIH HHS, Id: R01 AI046954-04
  • Agency: NIAID NIH HHS, Id: R01 AI046954-05
  • Agency: NIAID NIH HHS, Id: R01 AI46954
  • Agency: NCRR NIH HHS, Id: RR00168
  • Agency: NIAID NIH HHS, Id: U19 AI062623
  • Agency: NIAID NIH HHS, Id: U19 AI062623-050003
  • Agency: NIAID NIH HHS, Id: U19 AI083025
  • Agency: NIAID NIH HHS, Id: U19 AI62623
  • Agency: NIAID NIH HHS, Id: U54 AI057158
  • Agency: NIAID NIH HHS, Id: U54 AI057158-05S10003
  • Agency: NIAID NIH HHS, Id: U54 AI57158

Mesh Terms

  • Animals
  • Cell Line
  • DEAD-box RNA Helicases
  • Female
  • Host-Pathogen Interactions
  • Humans
  • Influenza A virus
  • Influenza, Human
  • Interferon Type I
  • Mice
  • Mice, Inbred BALB C
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Transport
  • Signal Transduction
  • Transcription Factors
  • Ubiquitin-Protein Ligases
  • Ubiquitination
  • Viral Nonstructural Proteins