TRIM25 in the Regulation of the Antiviral Innate Immunity

Martín-Vicente, María; Medrano, Luz María; Resino, Salvador; Garcı́a-Sastre, Adolfo; Martı́nez, Isidoro

doi:10.3389/fimmu.2017.01187

Cited by 120 publications

(105 citation statements)

References 115 publications

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“…Nature reviews | Immunology or transfection with poly(I:C) or RNA from HCV) 90,[93][94][95][96][97] . Given the important role of TRIM25 in RIG-I-mediated antiviral gene induction, several viral pathogens have evolved antagonists that directly inhibit TRIM25 activity, including NS1 from IAV 96,98 , NS1 from respiratory syncytial virus 99 , E6 from human papilloma virus 97 and the BPLF1 protein from Epstein-Barr virus 100 , or the subgenomic RNA of dengue virus 101 (reviewed in detail elsewhere 102,103 ). Moreover, in recent years several cellular proteins (for example, nuclear dbf2-related 2 (NDR2), zinc finger CCHC-type-containing 3 (ZCCHC3), NLR family pyrin domain-containing 12 (NLRP12) and caspase 12) that specifically regulate TRIM25's function in RIG-I K63-linked ubiquitylation have been identified (as described below).…”

Section: Single-nucleotide Polymorphismsmentioning

confidence: 99%

RIG-I-like receptors: their regulation and roles in RNA sensing

2020

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| Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are key sensors of virus infection, mediating the transcriptional induction of type I interferons and other genes that collectively establish an antiviral host response. Recent studies have revealed that both viral and host-derived RNAs can trigger RLR activation; this can lead to an effective antiviral response but also immunopathology if RLR activities are uncontrolled. In this Review , we discuss recent advances in our understanding of the types of RNA sensed by RLRs in the contexts of viral infection, malignancies and autoimmune diseases. We further describe how the activity of RLRs is controlled by host regulatory mechanisms, including RLR-interacting proteins, post-translational modifications and non-coding RNAs. Finally , we discuss key outstanding questions in the RLR field, including how our knowledge of RLR biology could be translated into new therapeutics.

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Section: Single-nucleotide Polymorphismsmentioning

confidence: 99%

RIG-I-like receptors: their regulation and roles in RNA sensing

2020

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“…Characterization of the immune response induced by different pathogens in murine alveolar macrophages infected at high MOI [40], showed a higher induction of TRIM25 expression in delNS1 infected cells compared with PR8 infection (data not shown). TRIM25-mediated ubiquitination stimulates RIG-I tetramerization, allowing RIG-I-MAVS interaction, which triggers the induction of the innate immune response [45][46][47]. The influenza virus expresses the NS1 protein, a multifunctional protein capable of counteracting the antiviral response [37].…”

Section: Discussionmentioning

confidence: 99%

Interferon-β Stimulation Elicited by the Influenza Virus Is Regulated by the Histone Methylase Dot1L through the RIG-I-TRIM25 Signaling Axis

Marcos-Villar

Zamarreño

Garaigorta

et al. 2020

Cells

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Influenza virus infection increases the methylation of lysine 79 of histone 3 catalyzed by the Dot1L enzyme. The role of Dot1L against infections was highlighted by an increase of influenza A and vesicular stomatitis virus replication in Dot1L-inhibited cells mediated by a decreased antiviral response. Interferon-beta (IFN-β) reporter assays indicate that Dot1L is involved in the control of retinoic acid-inducible gene-I protein (RIG-I) signaling. Accordingly, Dot1L inhibition decreases the IFN-β promoter stimulation and RIG-I-mitochondria-associated viral sensor (RIG-I-MAVS) association upon viral infection. Replication of an influenza A virus lacking NS1 (delNS1), incapable of counteracting the antiviral response, is not affected by Dot1L inhibition. Consequently, RIG-I-MAVS association and nuclear factor-κB (NF-κB) nuclear translocation, are not affected by the Dot1L inhibition in delNS1 infected cells. Restoration of NS1 expression in trans also reinstated Dot1L as a regulator of the RIG-I-dependent signaling in delNS1 infections. Interferon-inducible E3 ligase tripartite motif-containing protein 25 (TRIM25) expression increases in influenza virus infected cells, but Dot1L inhibition reduces both the TRIM25 expression and TRIM25 protein levels. TRIM25 overexpression reverses the defective innate response mediated by Dot1L inhibition elicited upon virus infection or by overexpression of RIG-I signaling intermediates. Thus, TRIM25 is a control point of the RIG-I recognition pathway controlled by Dot1L and may have a general role in RNA viruses recognized by the RIG-I sensor.Cells 2020, 9, 732 2 of 20 H1N1 virus-infected cells, we observed unaltered DNA methylation and a general decrease in histone acetylation, which correlates with the cell host transcriptional inactivation that takes place during infection.Unexpectedly, we observed an increase in the methylation of lysine 79 of histone 3 (H3K79) in the infected cells [5]. The methylation of H3K79 is carried out by the histone methylase Dot1L, which exclusively methylates this lysine, and its methylation is increased in actively transcribing genes [6,7]. The inhibition of Dot1l by pinometostat (EPZ) treatment or by Dot1L silencing, stimulated influenza and vesicular stomatitis virus replication [5]. Further characterization showed decreased nuclear translocation of the NF-kB complex, as well as IFN-β, Mx1 and ISG56 expression in EPZ-treated cells [5] indicating a decreased antiviral type I IFN response, and as a consequence, a stimulation in viral replication. Conversely, Dot1L overexpression reduced the multiplication of the virus [8].Invading viral RNAs are detected by different cytoplasmic sensors that promote type I IFN responses to elicit an antiviral state. Among the cytoplasmic RNA sensors, RIG-I plays a pivotal role in the recognition of negative-strand RNA viruses [9,10]. The melanoma differentiation-associated protein 5 (MDA5), has been involved in the recognition of the RNA of picornaviruses [11]. However, some viruses appear to be sensed by both . A...

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“…TRIM25 is an E3 ubiquitin ligase enzyme that can regulate the innate immune response against viruses (Martin-Vicente et al, 2017). TRIM25-mediated ubiquitination of the cytosolic PRR RIG-I is an essential step for the initiation of an intracellular antiviral response (Gack et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…After recognition, the N-terminal caspase recruitment domains (CARDs) of RIG-I are modified by ubiquitin which is mediated by TRIM25. Such modification is essential for activating a signaling cascade, ultimately resulting in the transcriptional activation of type I and III interferons (IFNs), mediating viral clearance, and inhibiting viral replication and spread (Gack et al, 2009;Martin-Vicente et al, 2017). Various viruses are inhibited by TRIM25, e.g., Coxsackie B virus and poliovirus (Schoggins et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Nucleocapsid protein of porcine reproductive and respiratory syndrome virus antagonizes the antiviral activity of TRIM25 by interfering with TRIM25-mediated RIG-I ubiquitination

Zhao

Jiang

et al. 2019

Veterinary Microbiology

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Porcine reproductive and respiratory syndrome (PRRS) is caused by PRRS virus (PRRSV), and is characterized by respiratory diseases in piglet and reproductive disorders in sow. Identification of sustainable and effective measures to mitigate PRRSV transmission is a pressing problem. The nucleocapsid (N) protein of PRRSV plays a crucial role in inhibiting host innate immunity during PRRSV infection. In the current study, a new host-restricted factor, tripartite motif protein 25 (TRIM25), was identified as an inhibitor of PRRSV replication. Coimmunoprecipitation assay indicated that the PRRSV N protein interferes with TRIM25-RIG-I interactions by competitively interacting with TRIM25. Furthermore, N protein inhibits the expression of TRIM25 and TRIM25mediated RIG-I ubiquitination to suppress interferon β production. Furthermore, with increasing TRIM25 expression, the inhibitory effect of N protein on the ubiquitination of RIG-I diminished. These results indicate for the first time that TRIM25 inhibits PRRSV replication and that the N protein antagonizes the antiviral activity by interfering with TRIM25-mediated RIG-I ubiquitination. This not only provides a theoretical basis for the development of drugs to control PRRSV replication, but also better explains the mechanism through which the PRRSV N protein inhibits innate immune responses of the host. ⁎

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TRIM25 in the Regulation of the Antiviral Innate Immunity

Cited by 120 publications

References 115 publications

RIG-I-like receptors: their regulation and roles in RNA sensing

RIG-I-like receptors: their regulation and roles in RNA sensing

Interferon-β Stimulation Elicited by the Influenza Virus Is Regulated by the Histone Methylase Dot1L through the RIG-I-TRIM25 Signaling Axis

Nucleocapsid protein of porcine reproductive and respiratory syndrome virus antagonizes the antiviral activity of TRIM25 by interfering with TRIM25-mediated RIG-I ubiquitination

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