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.
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
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
Cell Host Microbe
Date: May. 08, 2009
PubMed ID: 19454348
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