Viruses and the Ubiquitin/Proteasome System

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

Deadline for manuscript submissions: closed (31 March 2015) | Viewed by 65714

Special Issue Editor

1. Division of Protective Immunity and Division of Cancer Pathobiology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
2. Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Interests: virology; virus replication; DNA damage and repair; genome instability; viral vectors

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Published Papers (8 papers)

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Review

1250 KiB  
Review
Viral Mimicry to Usurp Ubiquitin and SUMO Host Pathways
by Peter Wimmer and Sabrina Schreiner
Viruses 2015, 7(9), 4854-4872; https://doi.org/10.3390/v7092849 - 28 Aug 2015
Cited by 49 | Viewed by 9108
Abstract
Posttranslational modifications (PTMs) of proteins include enzymatic changes by covalent addition of cellular regulatory determinants such as ubiquitin (Ub) and small ubiquitin-like modifier (SUMO) moieties. These modifications are widely used by eukaryotic cells to control the functional repertoire of proteins. Over the last [...] Read more.
Posttranslational modifications (PTMs) of proteins include enzymatic changes by covalent addition of cellular regulatory determinants such as ubiquitin (Ub) and small ubiquitin-like modifier (SUMO) moieties. These modifications are widely used by eukaryotic cells to control the functional repertoire of proteins. Over the last decade, it became apparent that the repertoire of ubiquitiylation and SUMOylation regulating various biological functions is not restricted to eukaryotic cells, but is also a feature of human virus families, used to extensively exploit complex host-cell networks and homeostasis. Intriguingly, besides binding to host SUMO/Ub control proteins and interfering with the respective enzymatic cascade, many viral proteins mimic key regulatory factors to usurp this host machinery and promote efficient viral outcomes. Advanced detection methods and functional studies of ubiquitiylation and SUMOylation during virus-host interplay have revealed that human viruses have evolved a large arsenal of strategies to exploit these specific PTM processes. In this review, we highlight the known viral analogs orchestrating ubiquitin and SUMO conjugation events to subvert and utilize basic enzymatic pathways. Full article
(This article belongs to the Special Issue Viruses and the Ubiquitin/Proteasome System)
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929 KiB  
Review
Hepatitis B Virus HBx Protein Interactions with the Ubiquitin Proteasome System
by Marissa M. Minor and Betty L. Slagle
Viruses 2014, 6(11), 4683-4702; https://doi.org/10.3390/v6114683 - 24 Nov 2014
Cited by 55 | Viewed by 11029
Abstract
The hepatitis B virus (HBV) causes acute and chronic hepatitis, and the latter is a major risk factor for the development of hepatocellular carcinoma (HCC). HBV encodes a 17-kDa regulatory protein, HBx, which is required for virus replication. Although the precise contribution(s) of [...] Read more.
The hepatitis B virus (HBV) causes acute and chronic hepatitis, and the latter is a major risk factor for the development of hepatocellular carcinoma (HCC). HBV encodes a 17-kDa regulatory protein, HBx, which is required for virus replication. Although the precise contribution(s) of HBx to virus replication is unknown, many viruses target cellular pathways to create an environment favorable for virus replication. The ubiquitin proteasome system (UPS) is a major conserved cellular pathway that controls several critical processes in the cell by regulating the levels of proteins involved in cell cycle, DNA repair, innate immunity, and other processes. We summarize here the interactions of HBx with components of the UPS, including the CUL4 adaptor DDB1, the cullin regulatory complex CSN, and the 26S proteasome. Understanding how these protein interactions benefit virus replication remains a challenge due to limited models in which to study HBV replication. However, studies from other viral systems that similarly target the UPS provide insight into possible strategies used by HBV. Full article
(This article belongs to the Special Issue Viruses and the Ubiquitin/Proteasome System)
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1178 KiB  
Review
Regulation of HTLV-1 Tax Stability, Cellular Trafficking and NF-κB Activation by the Ubiquitin-Proteasome Pathway
by Alfonso Lavorgna and Edward William Harhaj
Viruses 2014, 6(10), 3925-3943; https://doi.org/10.3390/v6103925 - 23 Oct 2014
Cited by 29 | Viewed by 7446
Abstract
Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that infects CD4+ T cells and causes adult T-cell leukemia/lymphoma (ATLL) in 3%–5% of infected individuals after a long latent period. HTLV-1 Tax is a trans-activating protein that regulates viral gene [...] Read more.
Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that infects CD4+ T cells and causes adult T-cell leukemia/lymphoma (ATLL) in 3%–5% of infected individuals after a long latent period. HTLV-1 Tax is a trans-activating protein that regulates viral gene expression and also modulates cellular signaling pathways to enhance T-cell proliferation and cell survival. The Tax oncoprotein promotes T-cell transformation, in part via constitutive activation of the NF-κB transcription factor; however, the underlying mechanisms remain unknown. Ubiquitination is a type of post-translational modification that occurs in a three-step enzymatic cascade mediated by E1, E2 and E3 enzymes and regulates protein stability as well as signal transduction, protein trafficking and the DNA damage response. Emerging studies indicate that Tax hijacks the ubiquitin machinery to activate ubiquitin-dependent kinases and downstream NF-κB signaling. Tax interacts with the E2 conjugating enzyme Ubc13 and is conjugated on C-terminal lysine residues with lysine 63-linked polyubiquitin chains. Tax K63-linked polyubiquitination may serve as a platform for signaling complexes since this modification is critical for interactions with NEMO and IKK. In addition to NF-κB signaling, mono- and polyubiquitination of Tax also regulate its subcellular trafficking and stability. Here, we review recent advances in the diverse roles of ubiquitin in Tax function and how Tax usurps the ubiquitin-proteasome pathway to promote oncogenesis. Full article
(This article belongs to the Special Issue Viruses and the Ubiquitin/Proteasome System)
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617 KiB  
Review
The Role of Ubiquitin and Ubiquitin-Like Modification Systems in Papillomavirus Biology
by Van G. Wilson
Viruses 2014, 6(9), 3584-3611; https://doi.org/10.3390/v6093584 - 24 Sep 2014
Cited by 8 | Viewed by 6361
Abstract
Human papillomaviruses (HPVs) are small DNA viruses that are important etiological agents of a spectrum of human skin lesions from benign to malignant. Because of their limited genome coding capacity they express only a small number of proteins, only one of which has [...] Read more.
Human papillomaviruses (HPVs) are small DNA viruses that are important etiological agents of a spectrum of human skin lesions from benign to malignant. Because of their limited genome coding capacity they express only a small number of proteins, only one of which has enzymatic activity. Additionally, the HPV productive life cycle is intimately tied to the epithelial differentiation program and they must replicate in what are normally non-replicative cells, thus, these viruses must reprogram the cellular environment to achieve viral reproduction. Because of these limitations and needs, the viral proteins have evolved to co-opt cellular processes primarily through protein-protein interactions with critical host proteins. The ubiquitin post-translational modification system and the related ubiquitin-like modifiers constitute a widespread cellular regulatory network that controls the levels and functions of thousands of proteins, making these systems an attractive target for viral manipulation. This review describes the interactions between HPVs and the ubiquitin family of modifiers, both to regulate the viral proteins themselves and to remodel the host cell to facilitate viral survival and reproduction. Full article
(This article belongs to the Special Issue Viruses and the Ubiquitin/Proteasome System)
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341 KiB  
Review
Posttranslational Modifications of HIV-1 Integrase by Various Cellular Proteins during Viral Replication
by Yingfeng Zheng and Xiaojian Yao
Viruses 2013, 5(7), 1787-1801; https://doi.org/10.3390/v5071787 - 16 Jul 2013
Cited by 23 | Viewed by 8811
Abstract
HIV-1 integrase (IN) is a key viral enzyme during HIV-1 replication that catalyzes the insertion of viral DNA into the host genome. Recent studies have provided important insights into the multiple posttranslational modifications (PTMs) of IN (e.g., ubiquitination, SUMOylation, acetylation and phosphorylation), which [...] Read more.
HIV-1 integrase (IN) is a key viral enzyme during HIV-1 replication that catalyzes the insertion of viral DNA into the host genome. Recent studies have provided important insights into the multiple posttranslational modifications (PTMs) of IN (e.g., ubiquitination, SUMOylation, acetylation and phosphorylation), which regulate its multifaceted functions. A number of host cellular proteins, including Lens Epithelium‑derived Growth factor (LEDGF/p75), p300 and Ku70 have been shown to interact with IN and be involved in the PTM process of IN, either facilitating or counteracting the IN PTMs. Although previous studies have revealed much about the important roles of IN PTMs, how IN functions are fine-tuned by these PTMs under the physiological setting still needs to be determined. Here, we review the advances in the understanding of the mechanisms and roles of multiple IN PTMs. Full article
(This article belongs to the Special Issue Viruses and the Ubiquitin/Proteasome System)
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286 KiB  
Review
What Has the Study of the K3 and K5 Viral Ubiquitin E3 Ligases Taught Us about Ubiquitin-Mediated Receptor Regulation?
by Jessica M. Boname and Paul J. Lehner
Viruses 2011, 3(2), 118-131; https://doi.org/10.3390/v3020118 - 28 Jan 2011
Cited by 42 | Viewed by 6447
Abstract
Cells communicate with each other and the outside world through surface receptors, which need to be tightly regulated to prevent both overstimulation and receptor desensitization. Understanding the processes involved in the homeostatic control of cell surface receptors is essential, but we are not [...] Read more.
Cells communicate with each other and the outside world through surface receptors, which need to be tightly regulated to prevent both overstimulation and receptor desensitization. Understanding the processes involved in the homeostatic control of cell surface receptors is essential, but we are not alone in trying to regulate these receptors. Viruses, as the ultimate host pathogens, have co-evolved over millions of years and have both pirated and adapted host genes to enable viral pathogenesis. K3 and K5 (also known as MIR1 and MIR2) are viral ubiquitin E3 ligases from Kaposi’s Sarcoma Associated Herpesvirus (KSHV) which decrease expression of a number of cell surface receptors and have been used to interrogate cellular processes and improve our understanding of ubiquitin-mediated receptor endocytosis and degradation. In this review, we summarize what has been learned from the study of these viral genes and emphasize their role in elucidating the complexity of ubiquitin in receptor regulation. Full article
(This article belongs to the Special Issue Viruses and the Ubiquitin/Proteasome System)
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549 KiB  
Review
Poxvirus Exploitation of the Ubiquitin-Proteasome System
by Michele Barry, Nicholas Van Buuren, Kristin Burles, Kelly Mottet, Qian Wang and Alastair Teale
Viruses 2010, 2(10), 2356-2380; https://doi.org/10.3390/v2102356 - 19 Oct 2010
Cited by 34 | Viewed by 7624
Abstract
Ubiquitination plays a critical role in many cellular processes. A growing number of viruses have evolved strategies to exploit the ubiquitin-proteasome system, including members of the Poxviridae family. Members of the poxvirus family have recently been shown to encode BTB/kelch and ankyrin/F-box proteins [...] Read more.
Ubiquitination plays a critical role in many cellular processes. A growing number of viruses have evolved strategies to exploit the ubiquitin-proteasome system, including members of the Poxviridae family. Members of the poxvirus family have recently been shown to encode BTB/kelch and ankyrin/F-box proteins that interact with cullin-3 and cullin-1 based ubiquitin ligases, respectively. Multiple members of the poxvirus family also encode ubiquitin ligases with intrinsic activity. This review describes the numerous mechanisms that poxviruses employ to manipulate the ubiquitin-proteasome system. Full article
(This article belongs to the Special Issue Viruses and the Ubiquitin/Proteasome System)
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198 KiB  
Review
Antiviral Properties of ISG15
by Deborah J. Lenschow
Viruses 2010, 2(10), 2154-2168; https://doi.org/10.3390/v2102154 - 28 Sep 2010
Cited by 45 | Viewed by 8222
Abstract
The type I interferon system plays a critical role in limiting the spread of viral infection. Viruses induce the production of interferon (IFN), which after binding to the IFN-α/β receptor (IFNAR), and triggering of the JAK/STAT signaling cascade, results in the induction of [...] Read more.
The type I interferon system plays a critical role in limiting the spread of viral infection. Viruses induce the production of interferon (IFN), which after binding to the IFN-α/β receptor (IFNAR), and triggering of the JAK/STAT signaling cascade, results in the induction of interferon-stimulated genes (ISGs). These ISGs function to inhibit viral replication and to regulate the host immune response. Among these ISGs, the ubiquitin-like molecule, ISG15, is one of the most strongly induced proteins. Similar to ubiquitin, through an IFN induced conjugation cascade, ISG15 is covalently linked to a variety of cellular proteins, suggesting regulation of different cellular processes. Studies performed over the past several years have shown that ISG15 plays a central role in the host’s antiviral response against many viruses. Mice lacking ISG15 display increased susceptibility to multiple viruses. Furthermore, several viruses have developed immune evasion strategies that directly target the ISG15 pathway. Work is now underway to determine the mechanism by which ISG15 functions as an antiviral molecule, such that therapies targeting this pathway can be developed in the future. Full article
(This article belongs to the Special Issue Viruses and the Ubiquitin/Proteasome System)
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