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.
Gack
Michaela U
MU
Department of Microbiology and Molecular Genetics and Tumor Virology Division, New England Primate Research Center, Harvard Medical School, 1 Pine Hill Drive, Southborough, Massachusetts 01772, USA.
Shin
Young C
YC
Joo
Chul-Hyun
CH
Urano
Tomohiko
T
Liang
Chengyu
C
Sun
Lijun
L
Takeuchi
Osamu
O
Akira
Shizuo
S
Chen
Zhijian
Z
Inoue
Satoshi
S
Jung
Jae U
JU
D020816:Amino Acid Motifs; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012328:RNA Viruses / Q000276:immunology*; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D016328:NF-kappa B; D025801:Ubiquitin; D016899:Interferon-beta; D044767:Ubiquitin-Protein Ligases; D053487:DEAD-box RNA Helicases