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

Abstract

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.

• Authors: Michaela U Gack, Young C Shin, Chul-Hyun Joo, Tomohiko Urano, Chengyu Liang, Lijun Sun, Osamu Takeuchi, Shizuo Akira, Zhijian Chen, Satoshi Inoue, Jae U Jung
• Journal: Nature (Nature) Vol. 446 Issue 7138 Pg. 916-920 (Apr 19 2007) ISSN: 1476-4687 [Electronic] England
• PMID: 17392790 (Publication Type: Letter, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• Ubiquitin
• Interferon-beta
• Ubiquitin-Protein Ligases
• DEAD-box RNA Helicases

Topics

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