Article

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

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.
Nature (Impact Factor: 41.46). 05/2007; 446(7138):916-920. DOI: 10.1038/nature05732
Source: PubMed

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.

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    • "Conversely, ubiquitination has no known role in MDA5 or LGP2 activation. The first virus-triggered RIG-I ubiquitination site described , K172, depends on the E3 activity of tripartite motif protein 25 (TRIM25; Gack et al., 2007). Plausibly as a means of restricting escape mutant selection, this activation mechanism now appears to have evolved with partial redundancy using alternate E3s. "
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    ABSTRACT: Viral infection activates danger signals that are transmitted via the retinoic acid-inducible gene 1-like receptor (RLR), nucleotide-binding oligomerization domain-like receptor (NLR), and Toll-like receptor (TLR) protein signaling cascades. This places host cells in an antiviral posture by up-regulating antiviral cytokines including type-I interferon (IFN-I). Ubiquitin modifications and cross-talk between proteins within these signaling cascades potentiate IFN-I expression, and inversely, a growing number of viruses are found to weaponize the ubiquitin modification system to suppress IFN-I. Here we review how host- and virus-directed ubiquitin modification of proteins in the RLR, NLR, and TLR antiviral signaling cascades modulate IFN-I expression.
    Preview · Article · Dec 2015 · Journal of Experimental Medicine
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    • "An increasing number of TRIM proteins have also been described as enhancers of innate immune pathways, as in the case for TRIM44, which stabilizes MAVS to enhance signaling (Yang et al., 2013). TRIM proteins mediate several types of ubiquitin linkages, and most studies focus on K48- and K63-based linkages and their respective roles in degradation and stabilization of protein complexes (Davis and Gack, 2015; Flannick et al., 2014; Gack et al., 2007; Rajsbaum et al., 2014b; Tsuchida et al., 2010; Zhao et al., 2012), although K27- linked ubiquitination has been reported for TRIM23 (Arimoto et al., 2010). Our findings of TRIM62-mediated K27-linked ubiquitination of CARD9 suggest that this type of linkage promotes an important mechanism for protein activation, although notably the K125R alteration does not affect colocalization of CARD9 and BCL10. "
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    ABSTRACT: CARD9 is a central component of anti-fungal innate immune signaling via C-type lectin receptors, and several immune-related disorders are associated with CARD9 alterations. Here, we used a rare CARD9 variant that confers protection against inflammatory bowel disease as an entry point to investigating CARD9 regulation. We showed that the protective variant of CARD9, which is C-terminally truncated, acted in a dominant-negative manner for CARD9-mediated cytokine production, indicating an important role for the C terminus in CARD9 signaling. We identified TRIM62 as a CARD9 binding partner and showed that TRIM62 facilitated K27-linked poly-ubiquitination of CARD9. We identified K125 as the ubiquitinated residue on CARD9 and demonstrated that this ubiquitination was essential for CARD9 activity. Furthermore, we showed that similar to Card9-deficient mice, Trim62-deficient mice had increased susceptibility to fungal infection. In this study, we utilized a rare protective allele to uncover a TRIM62-mediated mechanism for regulation of CARD9 activation.
    Full-text · Article · Oct 2015 · Immunity
    • "Considering the key role of K63-linked polyubiquitin in RIG-I antiviral signaling, we next studied the potential function of K63- linked ubiquitination in regulating the interaction of Npl4 with RIG-I CARDs. It is well established that the E3 ubiquitin ligase TRIM25 activates RIG-I by generation of K63-linked polyubiquitin chains covalently attached to K172 of RIG-I (Gack et al, 2007). Meanwhile, separated K63-linked polyubiquitin chains can bind to RIG-I noncovalently for synergistic activation (Zeng et al, 2010). "
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    ABSTRACT: RIG-I is a well-studied sensor of viral RNA that plays a key role in innate immunity. p97 regulates a variety of cellular events such as protein quality control, membrane reassembly, DNA repair, and the cell cycle. Here, we report a new role for p97 with Npl4-Ufd1 as its cofactor in reducing antiviral innate immune responses by facilitating proteasomal degradation of RIG-I. The p97 complex is able to directly bind both non-ubiquitinated RIG-I and the E3 ligase RNF125, promoting K48-linked ubiquitination of RIG-I at residue K181. Viral infection significantly strengthens the interaction between RIG-I and the p97 complex by a conformational change of RIG-I that exposes the CARDs and through K63-linked ubiquitination of these CARDs. Disruption of the p97 complex enhances RIG-I antiviral signaling. Consistently, administration of compounds targeting p97 ATPase activity was shown to inhibit viral replication and protect mice from vesicular stomatitis virus (VSV) infection. Overall, our study uncovered a previously unrecognized role for the p97 complex in protein ubiquitination and revealed the p97 complex as a potential drug target in antiviral therapy.
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