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Ubiquitin and Ubiquitin-Like Pathways in Viral Infection

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 46000

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Dr. Ricardo Rajsbaum

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Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
Interests: innate immunity to virus infection and immune signaling; Type-I interferons (IFN) and other cytokines; the E3-ubiquitin ligase Tripartite Motif (TRIM) family of proteins in immunity; 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, West Nile, and Influenza; virus–host interactions and viral pathogenesis via the ubiquitin system
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Dear Colleagues,

The Ubiquitin (Ub) system is a major conserved post-translational process critical in many cellular functions, including regulation of immunity, virus replication, and modulation of virus–host intercations. The function of ubiquitinated proteins depends on the linkage type of the polyubiquitin chain, the length of the chain, and the the presence of ubiquitin-binding domains (UBDs) on specific proteins. Ub conjugation requires an E1-activating enzyme, an E2-conjugase, and an E3-ligase, which transfers Ub to the target protein. Each of these factors can be exploited by viruses to enhance their replication. Since the Ub system is also critical for the activation of antiviral immune signaling, this raises the question regarding the importance of Ub in promoting virus replication versus its role in inducing antiviral responses. To develop antiviral strategies, we need a better understanding of which factors of the Ub system can be targeted to reduce virus replication and at the same time decrease immune pathology. Extensive research has been done on mechanisms used by viruses that promote the degradation of antiviral host factors through Ub-dependent mechanisms or inhibit innate immune signaling pathways by blocking ubiquitination of host signaling components. Previously unrecognized mechanisms include the presence of ubiquitinated viral proteins or unanchored (not-covalently attached) Ub in infectious virions, which help virus entry and replication. In this Special Issue, we will explore novel aspects of virus antagonism of the immune reponse by targeting the host ubiquitin machinery and how viruses hijack ubiquitin factors to enhance their replication, a mechanism that ultimetely can be targeted to design antiviral strategies.

Dr. Ricardo Rajsbaum
Guest Editor

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Keywords

innate immunity
Type-I interferons
inflammatory cytokines
Tripartite Motif (TRIM) proteins
ubiquitin
unanchored ubiquitin
ubiquitin-like proteins
SUMOylation
ISGylation
NEDDylation
virus antagonism
ubiquitin ligases and conjugating enzymes
virus adaptation
cell signaling
ubiquitin/proteasome system
autophagy

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Published Papers (10 papers)

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Research

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11 pages, 2069 KiB

Open AccessArticle

USP38 Inhibits Zika Virus Infection by Removing Envelope Protein Ubiquitination

by Yingchong Wang, Qin Li, Dingwen Hu, Daolong Gao, Wenbiao Wang, Kailang Wu and Jianguo Wu

Viruses 2021, 13(10), 2029; https://doi.org/10.3390/v13102029 - 8 Oct 2021

Cited by 15 | Viewed by 2555

Abstract

Zika virus (ZIKV) is a mosquito-borne flavivirus, and its infection may cause severe neurodegenerative diseases. The outbreak of ZIKV in 2015 in South America has caused severe human congenital and neurologic disorders. Thus, it is vitally important to determine the inner mechanism of ZIKV infection. Here, our data suggested that the ubiquitin-specific peptidase 38 (USP38) played an important role in host resistance to ZIKV infection, during which ZIKV infection did not affect USP38 expression. Mechanistically, USP38 bound to the ZIKV envelope (E) protein through its C-terminal domain and attenuated its K48-linked and K63-linked polyubiquitination, thereby repressed the infection of ZIKV. In addition, we found that the deubiquitinase activity of USP38 was essential to inhibit ZIKV infection, and the mutant that lacked the deubiquitinase activity of USP38 lost the ability to inhibit infection. In conclusion, we found a novel host protein USP38 against ZIKV infection, and this may represent a potential therapeutic target for the treatment and prevention of ZIKV infection. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Viral Infection)

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13 pages, 1954 KiB

Open AccessArticle

Ubiquitin Ligase SMURF2 Interacts with Filovirus VP40 and Promotes Egress of VP40 VLPs

by Ariel Shepley-McTaggart, Michael Patrick Schwoerer, Cari A. Sagum, Mark T. Bedford, Chaitanya K. Jaladanki, Hao Fan, Joel Cassel and Ronald N. Harty

Viruses 2021, 13(2), 288; https://doi.org/10.3390/v13020288 - 12 Feb 2021

Cited by 9 | Viewed by 3258

Abstract

Filoviruses Ebola (EBOV) and Marburg (MARV) are devastating high-priority pathogens capable of causing explosive outbreaks with high human mortality rates. The matrix proteins of EBOV and MARV, as well as eVP40 and mVP40, respectively, are the key viral proteins that drive virus assembly and egress and can bud independently from cells in the form of virus-like particles (VLPs). The matrix proteins utilize proline-rich Late (L) domain motifs (e.g., PPxY) to hijack specific host proteins that contain WW domains, such as the HECT family E3 ligases, to facilitate the last step of virus–cell separation. We identified E3 ubiquitin ligase Smad Ubiquitin Regulatory Factor 2 (SMURF2) as a novel interactor with VP40 that positively regulates VP40 VLP release. Our results show that eVP40 and mVP40 interact with the three WW domains of SMURF2 via their PPxY motifs. We provide evidence that the eVP40–SMURF2 interaction is functional as the expression of SMURF2 positively regulates VLP egress, while siRNA knockdown of endogenous SMURF2 decreases VLP budding compared to controls. In sum, our identification of novel interactor SMURF2 adds to the growing list of identified host proteins that can regulate PPxY-mediated egress of VP40 VLPs. A more comprehensive understanding of the modular interplay between filovirus VP40 and host proteins may lead to the development of new therapies to combat these deadly infections. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Viral Infection)

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Review

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18 pages, 1031 KiB

Open AccessReview

HERC5 and the ISGylation Pathway: Critical Modulators of the Antiviral Immune Response

by Nicholas A. Mathieu, Ermela Paparisto, Stephen D. Barr and Donald E. Spratt

Viruses 2021, 13(6), 1102; https://doi.org/10.3390/v13061102 - 9 Jun 2021

Cited by 34 | Viewed by 6363

Abstract

Mammalian cells have developed an elaborate network of immunoproteins that serve to identify and combat viral pathogens. Interferon-stimulated gene 15 (ISG15) is a 15.2 kDa tandem ubiquitin-like protein (UBL) that is used by specific E1–E2–E3 ubiquitin cascade enzymes to interfere with the activity of viral proteins. Recent biochemical studies have demonstrated how the E3 ligase HECT and RCC1-containing protein 5 (HERC5) regulates ISG15 signaling in response to hepatitis C (HCV), influenza-A (IAV), human immunodeficiency virus (HIV), SARS-CoV-2 and other viral infections. Taken together, the potent antiviral activity displayed by HERC5 and ISG15 make them promising drug targets for the development of novel antiviral therapeutics that can augment the host antiviral response. In this review, we examine the emerging role of ISG15 in antiviral immunity with a particular focus on how HERC5 orchestrates the specific and timely ISGylation of viral proteins in response to infection. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Viral Infection)

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14 pages, 2106 KiB

Open AccessReview

Contributions of Ubiquitin and Ubiquitination to Flaviviral Antagonism of Type I IFN

by Erika Hay-McCullough and Juliet Morrison

Viruses 2021, 13(5), 763; https://doi.org/10.3390/v13050763 - 27 Apr 2021

Cited by 4 | Viewed by 3066

Abstract

Flaviviruses implement a broad range of antagonism strategies against the host antiviral response. A pivotal component of the early host response is production and signaling of type I interferon (IFN-I). Ubiquitin, a prevalent cellular protein-modifying molecule, is heavily involved in the cellular regulation of this and other immune response pathways. Viruses use ubiquitin and ubiquitin machinery to antagonize various steps of these pathways through diverse mechanisms. Here, we highlight ways in which flaviviruses use or inhibit ubiquitin to antagonize the antiviral IFN-I response. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Viral Infection)

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49 pages, 1952 KiB

Open AccessReview

Negative Regulation of the Innate Immune Response through Proteasomal Degradation and Deubiquitination

by Valentina Budroni and Gijs A. Versteeg

Viruses 2021, 13(4), 584; https://doi.org/10.3390/v13040584 - 30 Mar 2021

Cited by 9 | Viewed by 5008

Abstract

The rapid and dynamic activation of the innate immune system is achieved through complex signaling networks regulated by post-translational modifications modulating the subcellular localization, activity, and abundance of signaling molecules. Many constitutively expressed signaling molecules are present in the cell in inactive forms, and become functionally activated once they are modified with ubiquitin, and, in turn, inactivated by removal of the same post-translational mark. Moreover, upon infection resolution a rapid remodeling of the proteome needs to occur, ensuring the removal of induced response proteins to prevent hyperactivation. This review discusses the current knowledge on the negative regulation of innate immune signaling pathways by deubiquitinating enzymes, and through degradative ubiquitination. It focusses on spatiotemporal regulation of deubiquitinase and E3 ligase activities, mechanisms for re-establishing proteostasis, and degradation through immune-specific feedback mechanisms vs. general protein quality control pathways. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Viral Infection)

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18 pages, 2697 KiB

Open AccessReview

Proteomic Approaches to Dissect Host SUMOylation during Innate Antiviral Immune Responses

by Marie Lork, Gauthier Lieber and Benjamin G. Hale

Viruses 2021, 13(3), 528; https://doi.org/10.3390/v13030528 - 23 Mar 2021

Cited by 3 | Viewed by 4263

Abstract

SUMOylation is a highly dynamic ubiquitin-like post-translational modification that is essential for cells to respond to and resolve various genotoxic and proteotoxic stresses. Virus infections also constitute a considerable stress scenario for cells, and recent research has started to uncover the diverse roles of SUMOylation in regulating virus replication, not least by impacting antiviral defenses. Here, we review some of the key findings of this virus-host interplay, and discuss the increasingly important contribution that large-scale, unbiased, proteomic methodologies are making to discoveries in this field. We highlight the latest proteomic technologies that have been specifically developed to understand SUMOylation dynamics in response to cellular stresses, and comment on how these techniques might be best applied to dissect the biology of SUMOylation during innate immunity. Furthermore, we showcase a selection of studies that have already used SUMO proteomics to reveal novel aspects of host innate defense against viruses, such as functional cross-talk between SUMO proteins and other ubiquitin-like modifiers, viral antagonism of SUMO-modified antiviral restriction factors, and an infection-triggered SUMO-switch that releases endogenous retroelement RNAs to stimulate antiviral interferon responses. Future research in this area has the potential to provide new and diverse mechanistic insights into host immune defenses. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Viral Infection)

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15 pages, 1075 KiB

Open AccessReview

The Role of the Host Ubiquitin System in Promoting Replication of Emergent Viruses

by Karl M. Valerdi, Adam Hage, Sarah van Tol, Ricardo Rajsbaum and Maria I. Giraldo

Viruses 2021, 13(3), 369; https://doi.org/10.3390/v13030369 - 26 Feb 2021

Cited by 32 | Viewed by 4608

Abstract

Ubiquitination of proteins is a post-translational modification process with many different cellular functions, including protein stability, immune signaling, antiviral functions and virus replication. While ubiquitination of viral proteins can be used by the host as a defense mechanism by destroying the incoming pathogen, viruses have adapted to take advantage of this cellular process. The ubiquitin system can be hijacked by viruses to enhance various steps of the replication cycle and increase pathogenesis. Emerging viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), flaviviruses like Zika and dengue, as well as highly pathogenic viruses like Ebola and Nipah, have the ability to directly use the ubiquitination process to enhance their viral-replication cycle, and evade immune responses. Some of these mechanisms are conserved among different virus families, especially early during virus entry, providing an opportunity to develop broad-spectrum antivirals. Here, we discuss the mechanisms used by emergent viruses to exploit the host ubiquitin system, with the main focus on the role of ubiquitin in enhancing virus replication. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Viral Infection)

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25 pages, 4290 KiB

Open AccessReview

TRIMming Type I Interferon-Mediated Innate Immune Response in Antiviral and Antitumor Defense

by Ling Wang and Shunbin Ning

Viruses 2021, 13(2), 279; https://doi.org/10.3390/v13020279 - 11 Feb 2021

Cited by 22 | Viewed by 5454

Abstract

The tripartite motif (TRIM) family comprises at least 80 members in humans, with most having ubiquitin or SUMO E3 ligase activity conferred by their N-terminal RING domain. TRIMs regulate a wide range of processes in ubiquitination- or sumoylation-dependent manners in most cases, and fewer as adaptors. Their roles in the regulation of viral infections, autophagy, cell cycle progression, DNA damage and other stress responses, and carcinogenesis are being increasingly appreciated, and their E3 ligase activities are attractive targets for developing specific immunotherapeutic strategies for immune diseases and cancers. Given their importance in antiviral immune response, viruses have evolved sophisticated immune escape strategies to subvert TRIM-mediated mechanisms. In this review, we focus on their regulation of IFN-I-mediated innate immune response, which plays key roles in antiviral and antitumor defense. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Viral Infection)

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14 pages, 825 KiB

Open AccessReview

Viral Evasion of RIG-I-Like Receptor-Mediated Immunity through Dysregulation of Ubiquitination and ISGylation

by Cindy Chiang, Guanqun Liu and Michaela U. Gack

Viruses 2021, 13(2), 182; https://doi.org/10.3390/v13020182 - 26 Jan 2021

Cited by 19 | Viewed by 5178

Abstract

Viral dysregulation or suppression of innate immune responses is a key determinant of virus-induced pathogenesis. Important sensors for the detection of virus infection are the RIG-I-like receptors (RLRs), which, in turn, are antagonized by many RNA viruses and DNA viruses. Among the different escape strategies are viral mechanisms to dysregulate the post-translational modifications (PTMs) that play pivotal roles in RLR regulation. In this review, we present the current knowledge of immune evasion by viral pathogens that manipulate ubiquitin- or ISG15-dependent mechanisms of RLR activation. Key viral strategies to evade RLR signaling include direct targeting of ubiquitin E3 ligases, active deubiquitination using viral deubiquitinating enzymes (DUBs), and the upregulation of cellular DUBs that regulate RLR signaling. Additionally, we summarize emerging new evidence that shows that enzymes of certain coronaviruses such as SARS-CoV-2, the causative agent of the current COVID-19 pandemic, actively deISGylate key molecules in the RLR pathway to escape type I interferon (IFN)-mediated antiviral responses. Finally, we discuss the possibility of targeting virally-encoded proteins that manipulate ubiquitin- or ISG15-mediated innate immune responses for the development of new antivirals and vaccines. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Viral Infection)

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17 pages, 2015 KiB

Open AccessReview

The Role of Ubiquitination in NF-κB Signaling during Virus Infection

by Kun Song and Shitao Li

Viruses 2021, 13(2), 145; https://doi.org/10.3390/v13020145 - 20 Jan 2021

Cited by 45 | Viewed by 4769

Abstract

The nuclear factor κB (NF-κB) family are the master transcription factors that control cell proliferation, apoptosis, the expression of interferons and proinflammatory factors, and viral infection. During viral infection, host innate immune system senses viral products, such as viral nucleic acids, to activate innate defense pathways, including the NF-κB signaling axis, thereby inhibiting viral infection. In these NF-κB signaling pathways, diverse types of ubiquitination have been shown to participate in different steps of the signal cascades. Recent advances find that viruses also modulate the ubiquitination in NF-κB signaling pathways to activate viral gene expression or inhibit host NF-κB activation and inflammation, thereby facilitating viral infection. Understanding the role of ubiquitination in NF-κB signaling during viral infection will advance our knowledge of regulatory mechanisms of NF-κB signaling and pave the avenue for potential antiviral therapeutics. Thus, here we systematically review the ubiquitination in NF-κB signaling, delineate how viruses modulate the NF-κB signaling via ubiquitination and discuss the potential future directions. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Viral Infection)

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