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TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity.

Retinoic-acid-inducible gene-I (RIG-I; also called DDX58) is a cytosolic viral RNA receptor that interacts with MAVS (also called VISA, IPS-1 or Cardif) to induce type I interferon-mediated host protective innate immunity against viral infection. Furthermore, members of the tripartite motif (TRIM) protein family, which contain a cluster of a RING-finger domain, a B box/coiled-coil domain and a SPRY domain, are involved in various cellular processes, including cell proliferation and antiviral activity. Here we report that the amino-terminal caspase recruitment domains (CARDs) of RIG-I undergo robust ubiquitination induced by TRIM25 in mammalian cells. The carboxy-terminal SPRY domain of TRIM25 interacts with the N-terminal CARDs of RIG-I; this interaction effectively delivers the Lys 63-linked ubiquitin moiety to the N-terminal CARDs of RIG-I, resulting in a marked increase in RIG-I downstream signalling activity. The Lys 172 residue of RIG-I is critical for efficient TRIM25-mediated ubiquitination and for MAVS binding, as well as the ability of RIG-I to induce antiviral signal transduction. Furthermore, gene targeting demonstrates that TRIM25 is essential not only for RIG-I ubiquitination but also for RIG-I-mediated interferon- production and antiviral activity in response to RNA virus infection. Thus, we demonstrate that TRIM25 E3 ubiquitin ligase induces the Lys 63-linked ubiquitination of RIG-I, which is crucial for the cytosolic RIG-I signalling pathway to elicit host antiviral innate immunity.

Pubmed ID: 17392790

Authors

  • Gack MU
  • Shin YC
  • Joo CH
  • Urano T
  • Liang C
  • Sun L
  • Takeuchi O
  • Akira S
  • Chen Z
  • Inoue S
  • Jung JU

Journal

Nature

Publication Data

April 19, 2007

Associated Grants

None

Mesh Terms

  • Amino Acid Motifs
  • Cell Line
  • DEAD-box RNA Helicases
  • Humans
  • Immunity, Innate
  • Interferon-beta
  • NF-kappa B
  • Protein Binding
  • Protein Structure, Tertiary
  • RNA Viruses
  • Signal Transduction
  • Ubiquitin
  • Ubiquitin-Protein Ligases