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TRIM Proteins in Antiviral Immunity and Virus Pathogenesis
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TRIM Proteins in Antiviral Immunity and Virus Pathogenesis

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (30 June 2024) | Viewed by 11029

Special Issue Editor

Dr. Ricardo Rajsbaum

E-Mail Website
Guest Editor
Center for Virus-Host-Innate Immunity and Department of Medicine; Rutgers Biomedical and Health Sciences, Institute for Infectious and Inflammatory Diseases, Rutgers University, Newark, NJ 07103, USA
Interests: innate immunity to virus infection and immune signaling; Type-I Interferons (IFN) and other inflammatory cytokines; the E3-ubiquitin ligase Tripartite Motif (TRIM) family of proteins in immunity and virus pathogenesis; the role of ubiquitin in immunity and virus replication; viral evasion mechanisms; the role of the ubiquitin system in replication of viruses including Ebola, Nipah, dengue, Zika, Influenza, and SARS-CoV-2; virus‒host interactions and viral pathogenesis via the ubiquitin system; emerging proviral roles of TRIM proteins
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Special Issue Information

Dear Colleagues,

Tripartite Motif (TRIM) proteins belong to a large family of E3-ubiquitin ligases, many of which have antiviral activity. TRIMs have long been known for their functions as direct restriction factors; however, they can also act indirectly by promoting the induction of antiviral type-I Interferons (IFN-I). TRIM activity has been linked to a variety of cellular functions, including the regulation of immune signaling, cell cycle, apoptosis, autophagy, and many others. Studies are uncovering unrecognized mechanisms of TRIM activity, including the direct ubiquitination of viral proteins that may balance proviral and antiviral functions, and may perform this via the synthesis of unconventional polyubiquitin chains. It is still unclear what mechanism balances the contradictory roles of TRIMs at the physiological level. The dual roles of TRIMs and their involvement in multiple cellular functions have made it virtually impossible to use them as feasible druggable targets. The generation of TRIM knockouts in cells and animals using CRISPR technology has led to an exponential advance in our understanding of TRIM functions. In this Special Issue, we will explore novel aspects of TRIM function in relation to virus infection, including proviral and antiviral roles, antagonism, and pathogenesis. New comprehensive studies may help identify novel strategies to modulate TRIM activity for therapeutic interventions.

Dr. Ricardo Rajsbaum
Guest Editor

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Keywords

  • Tripartite Motif (TRIM) proteins
  • E3-Ubiquitin ligases
  • innate immunity
  • antiviral restriction factors
  • proviral functions
  • Type-I Interferons (IFN-I)
  • inflammatory cytokines
  • ubiquitin
  • ubiquitin-like proteins
  • viral antagonism
  • autophagy
  • viral pathogenesis

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Published Papers (7 papers)

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Research

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27 pages, 8655 KiB  
Article
Interleukin 27, Similar to Interferons, Modulates Gene Expression of Tripartite Motif (TRIM) Family Members and Interferes with Mayaro Virus Replication in Human Macrophages
by Lady Johana Hernández-Sarmiento, Y. S. Tamayo-Molina, Juan Felipe Valdés-López and Silvio Urcuqui-Inchima
Viruses 2024, 16(6), 996; https://doi.org/10.3390/v16060996 - 20 Jun 2024
Cited by 1 | Viewed by 1664
Abstract
Background: The Tripartite motif (TRIM) family includes more than 80 distinct human genes. Their function has been implicated in regulating important cellular processes, including intracellular signaling, transcription, autophagy, and innate immunity. During viral infections, macrophages are key components of innate immunity that produce [...] Read more.
Background: The Tripartite motif (TRIM) family includes more than 80 distinct human genes. Their function has been implicated in regulating important cellular processes, including intracellular signaling, transcription, autophagy, and innate immunity. During viral infections, macrophages are key components of innate immunity that produce interferons (IFNs) and IL27. We recently published that IL27 and IFNs induce transcriptional changes in various genes, including those involved in JAK-STAT signaling. Furthermore, IL27 and IFNs share proinflammatory and antiviral pathways in monocyte-derived macrophages (MDMs), resulting in both common and unique expression of inflammatory factors and IFN-stimulated genes (ISGs) encoding antiviral proteins. Interestingly, many TRIM proteins have been recognized as ISGs in recent years. Although it is already very well described that TRIM expression is induced by IFNs, it is not fully understood whether TRIM genes are induced in macrophages by IL27. Therefore, in this study, we examined the effect of stimulation with IL27 and type I, II, and III IFNs on the mRNA expression profiles of TRIM genes in MDMs. Methods: We used bulk RNA-seq to examine the TRIM expression profile of MDMs treated with IFNs or IL27. Initially, we characterized the expression patterns of different TRIM subfamilies using a heatmap. Subsequently, a volcano plot was employed to identify commonly differentially expressed TRIM genes. Additionally, we conducted gene ontology analysis with ClueGO to explore the biological processes of the regulated TRIMs, created a gene-gene interaction network using GeneMANIA, and examined protein-protein interactions with the STRING database. Finally, RNA-seq data was validated using RT-qPCR. Furthermore, the effect of IL27 on Mayaro virus replication was also evaluated. Results: We found that IL27, similar to IFNs, upregulates several TRIM genes’ expression in human macrophages. Specifically, we identified three common TRIM genes (TRIM19, 21, and 22) induced by IL27 and all types of human IFNs. Additionally, we performed the first report of transcriptional regulation of TRIM19, 21, 22, and 69 genes in response to IL27. The TRIMs involved a broad range of biological processes, including defense response to viruses, viral life cycle regulation, and negative regulation of viral processes. In addition, we observed a decrease in Mayaro virus replication in MDMs previously treated with IL27. Conclusions: Our results show that IL27, like IFNs, modulates the transcriptional expression of different TRIM-family members involved in the induction of innate immunity and an antiviral response. In addition, the functional analysis demonstrated that, like IFN, IL27 reduced Mayaro virus replication in MDMs. This implies that IL27 and IFNs share many similarities at a functional level. Moreover, identifying distinct TRIM groups and their differential expressions in response to IL27 provides new insights into the regulatory mechanisms underlying the antiviral response in human macrophages. Full article
(This article belongs to the Special Issue TRIM Proteins in Antiviral Immunity and Virus Pathogenesis)
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17 pages, 2446 KiB  
Article
Pteropus vampyrus TRIM40 Is an Interferon-Stimulated Gene That Antagonizes RIG-I-like Receptors
by Sarah van Tol, Adam Hage, Ricardo Rajsbaum and Alexander N. Freiberg
Viruses 2023, 15(11), 2147; https://doi.org/10.3390/v15112147 - 25 Oct 2023
Cited by 2 | Viewed by 1830
Abstract
Nipah virus (NiV; genus: Henipavirus; family: Paramyxoviridae) naturally infects Old World fruit bats (family Pteropodidae) without causing overt disease. Conversely, NiV infection in humans and other mammals can be lethal. Comparing bat antiviral responses with those of humans may illuminate the [...] Read more.
Nipah virus (NiV; genus: Henipavirus; family: Paramyxoviridae) naturally infects Old World fruit bats (family Pteropodidae) without causing overt disease. Conversely, NiV infection in humans and other mammals can be lethal. Comparing bat antiviral responses with those of humans may illuminate the mechanisms that facilitate bats’ tolerance. Tripartite motif proteins (TRIMs), a large family of E3-ubiquitin ligases, fine-tune innate antiviral immune responses, and two human TRIMs interact with Henipavirus proteins. We hypothesize that NiV infection induces the expression of an immunosuppressive TRIM in bat, but not human cells, to promote tolerance. Here, we show that TRIM40 is an interferon-stimulated gene (ISG) in pteropodid but not human cells. Knockdown of bat TRIM40 increases gene expression of IFNβ, ISGs, and pro-inflammatory cytokines following poly(I:C) transfection. In Pteropus vampyrus, but not human cells, NiV induces TRIM40 expression within 16 h after infection, and knockdown of TRIM40 correlates with reduced NiV titers as compared to control cells. Bats may have evolved to express TRIM40 in response to viral infections to control immunopathogenesis. Full article
(This article belongs to the Special Issue TRIM Proteins in Antiviral Immunity and Virus Pathogenesis)
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Review

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20 pages, 1006 KiB  
Review
TRIM Proteins: Key Regulators of Immunity to Herpesvirus Infection
by Zuberwasim Sayyad, Dhiraj Acharya and Michaela U. Gack
Viruses 2024, 16(11), 1738; https://doi.org/10.3390/v16111738 - 6 Nov 2024
Viewed by 858
Abstract
Herpesviruses are ubiquitous DNA viruses that can establish latency and cause a range of mild to life-threatening diseases in humans. Upon infection, herpesviruses trigger the activation of several host antiviral defense programs that play critical roles in curbing virus replication and dissemination. Recent [...] Read more.
Herpesviruses are ubiquitous DNA viruses that can establish latency and cause a range of mild to life-threatening diseases in humans. Upon infection, herpesviruses trigger the activation of several host antiviral defense programs that play critical roles in curbing virus replication and dissemination. Recent work from many groups has integrated our understanding of TRIM (tripartite motif) proteins, a specific group of E3 ligase enzymes, as pivotal orchestrators of mammalian antiviral immunity. In this review, we summarize recent advances in the modulation of innate immune signaling by TRIM proteins during herpesvirus infection, with a focus on the detection of herpes simplex virus type 1 (HSV-1, a prototype herpesvirus) by cGAS-STING, RIG-I-like receptors, and Toll-like receptors. We also review the latest progress in understanding the intricate relationship between herpesvirus replication and TRIM protein-regulated autophagy and apoptosis. Finally, we discuss the maneuvers used by HSV-1 and other herpesviruses to overcome TRIM protein-mediated virus restriction. Full article
(This article belongs to the Special Issue TRIM Proteins in Antiviral Immunity and Virus Pathogenesis)
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21 pages, 4207 KiB  
Review
TRIM Proteins and Antiviral Microtubule Reorganization: A Novel Component in Innate Immune Responses?
by Charlotte Vadon, Maria Magda Magiera and Andrea Cimarelli
Viruses 2024, 16(8), 1328; https://doi.org/10.3390/v16081328 - 20 Aug 2024
Viewed by 1425
Abstract
TRIM proteins are a family of innate immune factors that play diverse roles in innate immunity and protect the cell against viral and bacterial aggression. As part of this special issue on TRIM proteins, we will take advantage of our findings on TRIM69, [...] Read more.
TRIM proteins are a family of innate immune factors that play diverse roles in innate immunity and protect the cell against viral and bacterial aggression. As part of this special issue on TRIM proteins, we will take advantage of our findings on TRIM69, which acts by reorganizing the microtubules (MTs) in a manner that is fundamentally antiviral, to more generally discuss how host–pathogen interactions that take place for the control of the MT network represent a crucial facet of the struggle that opposes viruses to their cell environment. In this context, we will present several other TRIM proteins that are known to interact with microtubules in situations other than viral infection, and we will discuss evidence that may suggest a possible contribution to viral control. Overall, the present review will highlight the importance that the control of the microtubule network bears in host–pathogen interactions. Full article
(This article belongs to the Special Issue TRIM Proteins in Antiviral Immunity and Virus Pathogenesis)
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13 pages, 3027 KiB  
Review
The Dual Role of TRIM7 in Viral Infections
by Maria Gonzalez-Orozco, Carlos A. Rodriguez-Salazar and Maria I. Giraldo
Viruses 2024, 16(8), 1285; https://doi.org/10.3390/v16081285 - 12 Aug 2024
Viewed by 1024
Abstract
The E3 ubiquitin ligase TRIM7 is known to have dual roles during viral infections. Like other TRIM proteins, TRIM7 can regulate the IFN pathway via the regulation of the cytosolic receptors RIG-I or MDA-5, which promote the production of type I interferons (IFN-I) [...] Read more.
The E3 ubiquitin ligase TRIM7 is known to have dual roles during viral infections. Like other TRIM proteins, TRIM7 can regulate the IFN pathway via the regulation of the cytosolic receptors RIG-I or MDA-5, which promote the production of type I interferons (IFN-I) and antiviral immune responses. Alternatively, under certain infectious conditions, TRIM7 can negatively regulate IFN-I signaling, resulting in increased virus replication. A growing body of evidence has also shown that TRIM7 can, in some cases, ubiquitinate viral proteins to promote viral replication and pathogenesis, while in other cases it can promote degradation of viral proteins through the proteasome, reducing virus infection. TRIM7 can also regulate the host inflammatory response and modulate the production of inflammatory cytokines, which can lead to detrimental inflammation. TRIM7 can also protect the host during infection by reducing cellular apoptosis. Here, we discuss the multiple functions of TRIM7 during viral infections and its potential as a therapeutic target. Full article
(This article belongs to the Special Issue TRIM Proteins in Antiviral Immunity and Virus Pathogenesis)
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17 pages, 1270 KiB  
Review
TRIMming down Flavivirus Infections
by Marion Cannac and Sébastien Nisole
Viruses 2024, 16(8), 1262; https://doi.org/10.3390/v16081262 - 6 Aug 2024
Viewed by 1153
Abstract
Flaviviruses comprise a large number of arthropod-borne viruses, some of which are associated with life-threatening diseases. Flavivirus infections are rising worldwide, mainly due to the proliferation and geographical expansion of their vectors. The main human pathogens are mosquito-borne flaviviruses, including dengue virus, Zika [...] Read more.
Flaviviruses comprise a large number of arthropod-borne viruses, some of which are associated with life-threatening diseases. Flavivirus infections are rising worldwide, mainly due to the proliferation and geographical expansion of their vectors. The main human pathogens are mosquito-borne flaviviruses, including dengue virus, Zika virus, and West Nile virus, but tick-borne flaviviruses are also emerging. As with any viral infection, the body’s first line of defense against flavivirus infections is the innate immune defense, of which type I interferon is the armed wing. This cytokine exerts its antiviral activity by triggering the synthesis of hundreds of interferon-induced genes (ISGs), whose products can prevent infection. Among the ISGs that inhibit flavivirus replication, certain tripartite motif (TRIM) proteins have been identified. Although involved in other biological processes, TRIMs constitute a large family of antiviral proteins active on a wide range of viruses. Furthermore, whereas some TRIM proteins directly block viral replication, others are positive regulators of the IFN response. Therefore, viruses have developed strategies to evade or counteract TRIM proteins, and some even hijack certain TRIM proteins to their advantage. In this review, we summarize the current state of knowledge on the interactions between flaviviruses and TRIM proteins, covering both direct and indirect antiviral mechanisms. Full article
(This article belongs to the Special Issue TRIM Proteins in Antiviral Immunity and Virus Pathogenesis)
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17 pages, 2098 KiB  
Review
Regulation of Mitochondria-Derived Immune Activation by ‘Antiviral’ TRIM Proteins
by Seeun Oh and Michael A. Mandell
Viruses 2024, 16(7), 1161; https://doi.org/10.3390/v16071161 - 19 Jul 2024
Viewed by 1813
Abstract
Mitochondria are key orchestrators of antiviral responses that serve as platforms for the assembly and activation of innate immune-signaling complexes. In response to viral infection, mitochondria can be triggered to release immune-stimulatory molecules that can boost interferon production. These same molecules can be [...] Read more.
Mitochondria are key orchestrators of antiviral responses that serve as platforms for the assembly and activation of innate immune-signaling complexes. In response to viral infection, mitochondria can be triggered to release immune-stimulatory molecules that can boost interferon production. These same molecules can be released by damaged mitochondria to induce pathogenic, antiviral-like immune responses in the absence of infection. This review explores how members of the tripartite motif-containing (TRIM) protein family, which are recognized for their roles in antiviral defense, regulate mitochondria-based innate immune activation. In antiviral defense, TRIMs are essential components of immune signal transduction pathways and function as directly acting viral restriction factors. TRIMs carry out conceptually similar activities when controlling immune activation related to mitochondria. First, they modulate immune-signaling pathways that can be activated by mitochondrial molecules. Second, they co-ordinate the direct removal of mitochondria and associated immune-activating factors through mitophagy. These insights broaden the scope of TRIM actions in innate immunity and may implicate TRIMs in diseases associated with mitochondria-derived inflammation. Full article
(This article belongs to the Special Issue TRIM Proteins in Antiviral Immunity and Virus Pathogenesis)
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