The E3 Ubiquitin Ligase TRIM40 Attenuates Antiviral Immune Responses by Targeting MDA5 and RIG-I

Zhao, Chenyang; Jia, Mutian; Song, Hui; Yu, Zhongxia; Wang, Wenwen; Li, Qi; Zhang, Lining; Zhao, Wei; Cao, Xuetao

doi:10.1016/j.celrep.2017.10.020

Cited by 117 publications

(106 citation statements)

References 50 publications

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“…Several E3 ligases other than TRIM25 promote ubiquitination of RIG-I leading to controversial discussions about their relative importance (64)(65)(66)(67)(68)(69). Among these are several TRIM proteins (TRIM4, 15,40) and Riplet, a close relative of TRIM25, that lost the B-Box domains and parts of the CC (70)(71)(72). Mechanistically, a sequential ubiquitination of RIG-I by first Riplet in the CTD and then TRIM25 at the CARDs has been proposed (68).…”

Section: Discussionmentioning

confidence: 99%

Mechanistic insights into RNA binding and RNA-regulated RIG-I ubiquitination by TRIM25

Haubrich

Augsten²,

Álvarez³

et al. 2020

Preprint

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TRIM25 is a ubiquitin E3 ligase active in innate immunity and cell fate decisions. Mounting evidence suggests that TRIM25’s E3 ligase activity is regulated by RNAs. However, while mutations affecting RNA-binding have been described, the precise RNA binding site has not been identified nor which domains are involved. Here, we present biophysical evidence for the presence of RNA binding sites on both TRIM25 PRY/SPRY and coiled-coil domains, and map the binding site on the PRY/SPRY with residue resolution. Cooperative RNA-binding of both domains enhances their otherwise transient interaction in solution and increases the E3 ligase activity of TRIM25. Mutational analysis shows that RNA binding affects ubiquitination of RIG-I in mammalian cells. In addition, we present a simple model system for RNA-induced liquid-liquid phase separation of TRIM25 in vitro, resembling previously observed cellular RNA granules, that facilitates the recruitment of RIG-I.

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Section: Discussionmentioning

confidence: 99%

Mechanistic insights into RNA binding and RNA-regulated RIG-I ubiquitination by TRIM25

Haubrich

Augsten²,

Álvarez³

et al. 2020

Preprint

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“…6) [160,161]. For TRIM40, this dampening of the antiviral immune response involved an interaction between its CC domain and the 2CARD domain of MDA5, leading to its K27-and K48-linked polyubiquitination and removal via the proteasome [161]. Impairment of both vRNA and vDNA sensing pathways by a single TRIM highlight how host homeostasis mechanisms are exploited by various pathogens.…”

Section: Negative Regulation Of Host Antiviral Signallingmentioning

confidence: 99%

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

Hage

Rajsbaum

2019

Journal of General Virology

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The innate immune system responds rapidly to protect against viral infections, but an overactive response can cause harmful damage. To avoid this, the response is tightly regulated by post-translational modifications (PTMs). The ubiquitin system represents a powerful PTM machinery that allows for the reversible linkage of ubiquitin to activate and deactivate a target's function. A precise enzymatic cascade of ubiquitin-activating, conjugating and ligating enzymes facilitates ubiquitination. Viruses have evolved to take advantage of the ubiquitin pathway either by targeting factors to dampen the antiviral response or by hijacking the system to enhance their replication. The tripartite motif (TRIM) family of E3 ubiquitin ligases has garnered attention as a major contributor to innate immunity. Many TRIM family members limit viruses either indirectly as components in innate immune signalling, or directly by targeting viral proteins for degradation. In spite of this, TRIMs and other ubiquitin ligases can be appropriated by viruses and repurposed as valuable tools in viral replication. This duality of function suggests a new frontier of research for TRIMs and raises new challenges for discerning the subtleties of these pro-viral mechanisms. Here, we review current findings regarding the involvement of TRIMs in host-virus interactions. We examine ongoing developments in the field, including novel roles for unanchored ubiquitin in innate immunity, the direct involvement of ubiquitin ligases in promoting viral replication, recent controversies on the role of ubiquitin and TRIM25 in activation of the pattern recognition receptor RIG-I, and we discuss the implications these studies have on future research directions.

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“…For example, TRIM5, TRIM21, TRIM23, TRIM31, TRIM32, TRIM56, and TRIM65 are reported to positively regulate the type I IFN pathway (7,8,11,(28)(29)(30)(31). Some TRIM proteins, like TRIM26 and TRIM40 are reported to act as negative regulators for innate immune responses (32,33). Among them, mammalian TRIM32 have been well-elucidated for its critical roles in regulating antiviral innate immune responses (11).…”

Section: Discussionmentioning

confidence: 99%

Duck TRIM32 Functions in IFN-β Signaling Against the Infection of H5N6 Highly Pathogenic Avian Influenza Virus

Zhang

Xue

et al. 2020

Front. Immunol.

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In mammals, tripartite motif 32 (TRIM32) is essential for regulating host innate immune responses to viral infections. However, the antiviral effect of TRIM32 in birds has not been reported. Here, we cloned the full-length duck TRIM32 (duTRIM32) cDNA from total spleen RNA of Peking duck. DuTRIM32 consists of 682 amino acids and has 95.5% similarity in amino acid sequences with chicken TRIM32 and 84.9% similarity with human TRIM32, respectively. DuTRIM32 mRNA was found to be ubiquitously expressed in all tested tissues from healthy ducks. Overexpression of duTRIM32 significantly activated the IFN-β promoter and upregulated the mRNA levels of IFN-β, IRF7, and Mx, which indicates that duTRIM32 is involved in the type I IFN pathway. Furthermore, duTRIM32 was found to directly interact with duck STING (duSTING) and to contribute to the expression of IFN-β mediated by duSTING. The mRNA level of duTRIM32 was significantly upregulated in the lungs and spleens of H5N6 highly pathogenic avian influenza virus (HPAIV) infected ducks 3 days post-infection (DPI). Furthermore, overexpression of duTRIM32 could inhibit the replication of H5N6 HPAIV in duck embryo fibroblasts (DEFs). Therefore, these results indicate that duTRIM32 is involved in the type I IFN pathway and exhibit an antiviral effect against H5N6 HPAIV infection.

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The E3 Ubiquitin Ligase TRIM40 Attenuates Antiviral Immune Responses by Targeting MDA5 and RIG-I

Cited by 117 publications

References 50 publications

Mechanistic insights into RNA binding and RNA-regulated RIG-I ubiquitination by TRIM25

Mechanistic insights into RNA binding and RNA-regulated RIG-I ubiquitination by TRIM25

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

Duck TRIM32 Functions in IFN-β Signaling Against the Infection of H5N6 Highly Pathogenic Avian Influenza Virus

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