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7.3
3.8
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Viruses
Special Issues
Viruses, ERAD, and the Proteasome
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Viruses, ERAD, and the Proteasome

A special issue of Viruses (ISSN 1999-4915).

Deadline for manuscript submissions: closed (31 July 2016) | Viewed by 59448

Special Issue Editors

Prof. Dr. Jaquelin P. Dudley

E-Mail Website
Guest Editor
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA
Interests: APOBECs; cytidine deaminase; AID; viral antagonists; viral hypermutation; innate immunity; viral selection
Special Issues, Collections and Topics in MDPI journals
Dr. Jason B. Weinberg

E-Mail Website
Co-Guest Editor
Department of Pediatrics and Communicable Diseases, Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America
Interests: Pathogenesis of adenovirus infections

Special Issue Information

Dear Colleagues,

Multiple viruses subvert ERAD to promote their replication. In some cases, ERAD is used for viral delivery into the cytosol, whereas other viruses encode proteins that target specific cellular proteins for degradation to prevent an anti-viral immune response. Viruses also may use the ERAD machinery for trafficking of specific viral proteins without triggering proteasomal degradation.

Degradation of damaged or misfolded proteins is an essential homeostatic process that is largely driven by the activity of the ubiquitin-proteasome system (UPS). UPS activity contributes to numerous critical cellular functions, such as signal transduction, cell signaling, antigen processing, regulation of cell cycle, and apoptosis. UPS activity is required for efficient replication of many viruses, but UPS activity also drives aspects of host defense that may limit viral replication. Not surprisingly, many viruses have evolved mechanisms to exploit or subvert the UPS in ways that provide an advantage for growth/survival.

For this Special Issue of Viruses, we aim to explore the various mechanisms that viruses use to manipulate ERAD and assemble a collection of research papers and reviews that together offer a comprehensive view on this field. Topics may include studies on the UPS and viral replication, host cell interactions, virus persistence and virus-associated oncogenesis, innate and adaptive immune responses to infection and mechanisms of immunoevasion, and other related aspects of proteasome activity and viral pathogenesis. We hope that this work will expand our current understanding of the intimate relationship between Viruses, ERAD, and UPS.

Prof. Jaquelin Dudley 
Guest Editor
Dr. Jason B. Weinberg
Co-Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • ERAD
  • retrotranslocation
  • ubiquitination
  • proteasomal degradation
  • viral entry
  • innate immunity
  • adaptive immunity
  • protein trafficking

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Published Papers (7 papers)

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Research

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1955 KiB  
Article
Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes
by Christian Setz, Melanie Friedrich, Pia Rauch, Kirsten Fraedrich, Alina Matthaei, Maximilian Traxdorf and Ulrich Schubert
Viruses 2017, 9(8), 222; https://doi.org/10.3390/v9080222 - 12 Aug 2017
Cited by 28 | Viewed by 8258
Abstract
In recent years it has been well established that two major constituent parts of the ubiquitin proteasome system (UPS)—the proteasome holoenzymes and a number of ubiquitin ligases—play a crucial role, not only in virus replication but also in the regulation of the immunogenicity [...] Read more.
In recent years it has been well established that two major constituent parts of the ubiquitin proteasome system (UPS)—the proteasome holoenzymes and a number of ubiquitin ligases—play a crucial role, not only in virus replication but also in the regulation of the immunogenicity of human immunodeficiency virus type 1 (HIV-1). However, the role in HIV-1 replication of the third major component, the deubiquitinating enzymes (DUBs), has remained largely unknown. In this study, we show that the DUB-inhibitors (DIs) P22077 and PR-619, specific for the DUBs USP7 and USP47, impair Gag processing and thereby reduce the infectivity of released virions without affecting viral protease activity. Furthermore, the replication capacity of X4- and R5-tropic HIV-1NL4-3 in human lymphatic tissue is decreased upon treatment with these inhibitors without affecting cell viability. Most strikingly, combinatory treatment with DIs and proteasome inhibitors synergistically blocks virus replication at concentrations where mono-treatment was ineffective, indicating that DIs can boost the therapeutic effect of proteasome inhibitors. In addition, P22077 and PR-619 increase the polyubiquitination of Gag and thus its entry into the UPS and the major histocompatibility complex (MHC)-I pathway. In summary, our data point towards a model in which specific inhibitors of DUBs not only interfere with virus spread but also increase the immune recognition of HIV-1 expressing cells. Full article
(This article belongs to the Special Issue Viruses, ERAD, and the Proteasome)
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3641 KiB  
Article
The E3 Ubiquitin Ligase TMEM129 Is a Tri-Spanning Transmembrane Protein
by Michael L. Van de Weijer, Guus H. Van Muijlwijk, Linda J. Visser, Ana I. Costa, Emmanuel J. H. J. Wiertz and Robert Jan Lebbink
Viruses 2016, 8(11), 309; https://doi.org/10.3390/v8110309 - 15 Nov 2016
Cited by 4 | Viewed by 6455
Abstract
Misfolded proteins from the endoplasmic reticulum (ER) are transported back into the cytosol for degradation via the ubiquitin-proteasome system. The human cytomegalovirus protein US11 hijacks this ER-associated protein degradation (ERAD) pathway to downregulate human leukocyte antigen (HLA) class I molecules in virus-infected cells, [...] Read more.
Misfolded proteins from the endoplasmic reticulum (ER) are transported back into the cytosol for degradation via the ubiquitin-proteasome system. The human cytomegalovirus protein US11 hijacks this ER-associated protein degradation (ERAD) pathway to downregulate human leukocyte antigen (HLA) class I molecules in virus-infected cells, thereby evading elimination by cytotoxic T-lymphocytes. Recently, we identified the E3 ubiquitin ligase transmembrane protein 129 (TMEM129) as a key player in this process, where interference with TMEM129 activity in human cells completely abrogates US11-mediated class I degradation. Here, we set out to further characterize TMEM129. We show that TMEM129 is a non-glycosylated protein containing a non-cleaved signal anchor sequence. By glycosylation scanning mutagenesis, we show that TMEM129 is a tri-spanning ER-membrane protein that adopts an Nexo–Ccyto orientation. This insertion in the ER membrane positions the C-terminal really interesting new gene (RING) domain of TMEM129 in the cytosol, making it available to catalyze ubiquitination reactions that are required for cytosolic degradation of secretory proteins. Full article
(This article belongs to the Special Issue Viruses, ERAD, and the Proteasome)
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Review

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2336 KiB  
Review
Therapeutic Strategies against Epstein-Barr Virus-Associated Cancers Using Proteasome Inhibitors
by Kwai Fung Hui, Kam Pui Tam and Alan Kwok Shing Chiang
Viruses 2017, 9(11), 352; https://doi.org/10.3390/v9110352 - 21 Nov 2017
Cited by 16 | Viewed by 7053
Abstract
Epstein-Barr virus (EBV) is closely associated with several lymphomas (endemic Burkitt lymphoma, Hodgkin lymphoma and nasal NK/T-cell lymphoma) and epithelial cancers (nasopharyngeal carcinoma and gastric carcinoma). To maintain its persistence in the host cells, the virus manipulates the ubiquitin-proteasome system to regulate viral [...] Read more.
Epstein-Barr virus (EBV) is closely associated with several lymphomas (endemic Burkitt lymphoma, Hodgkin lymphoma and nasal NK/T-cell lymphoma) and epithelial cancers (nasopharyngeal carcinoma and gastric carcinoma). To maintain its persistence in the host cells, the virus manipulates the ubiquitin-proteasome system to regulate viral lytic reactivation, modify cell cycle checkpoints, prevent apoptosis and evade immune surveillance. In this review, we aim to provide an overview of the mechanisms by which the virus manipulates the ubiquitin-proteasome system in EBV-associated lymphoid and epithelial malignancies, to evaluate the efficacy of proteasome inhibitors on the treatment of these cancers and discuss potential novel viral-targeted treatment strategies against the EBV-associated cancers. Full article
(This article belongs to the Special Issue Viruses, ERAD, and the Proteasome)
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3713 KiB  
Review
Hijacking of the Ubiquitin/Proteasome Pathway by the HIV Auxiliary Proteins
by Tanja Seissler, Roland Marquet and Jean-Christophe Paillart
Viruses 2017, 9(11), 322; https://doi.org/10.3390/v9110322 - 31 Oct 2017
Cited by 52 | Viewed by 13789
Abstract
The ubiquitin-proteasome system (UPS) ensures regulation of the protein pool in the cell by ubiquitination of proteins followed by their degradation by the proteasome. It plays a central role in the cell under normal physiological conditions as well as during viral infections. On [...] Read more.
The ubiquitin-proteasome system (UPS) ensures regulation of the protein pool in the cell by ubiquitination of proteins followed by their degradation by the proteasome. It plays a central role in the cell under normal physiological conditions as well as during viral infections. On the one hand, the UPS can be used by the cell to degrade viral proteins, thereby restricting the viral infection. On the other hand, it can also be subverted by the virus to its own advantage, notably to induce degradation of cellular restriction factors. This makes the UPS a central player in viral restriction and counter-restriction. In this respect, the human immunodeficiency viruses (HIV-1 and 2) represent excellent examples. Indeed, many steps of the HIV life cycle are restricted by cellular proteins, some of which are themselves components of the UPS. However, HIV itself hijacks the UPS to mediate defense against several cellular restriction factors. For example, the HIV auxiliary proteins Vif, Vpx and Vpu counteract specific restriction factors by the recruitment of cellular UPS components. In this review, we describe the interplay between HIV and the UPS to illustrate its role in the restriction of viral infections and its hijacking by viral proteins for counter-restriction. Full article
(This article belongs to the Special Issue Viruses, ERAD, and the Proteasome)
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934 KiB  
Review
Gammaherpesviral Tegument Proteins, PML-Nuclear Bodies and the Ubiquitin-Proteasome System
by Florian Full, Alexander S. Hahn, Anna K. Großkopf and Armin Ensser
Viruses 2017, 9(10), 308; https://doi.org/10.3390/v9100308 - 21 Oct 2017
Cited by 6 | Viewed by 7828
Abstract
Gammaherpesviruses like Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) subvert the ubiquitin proteasome system for their own benefit in order to facilitate viral gene expression and replication. In particular, viral tegument proteins that share sequence homology to the formylglycineamide ribonucleotide amidotransferase (FGARAT, [...] Read more.
Gammaherpesviruses like Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) subvert the ubiquitin proteasome system for their own benefit in order to facilitate viral gene expression and replication. In particular, viral tegument proteins that share sequence homology to the formylglycineamide ribonucleotide amidotransferase (FGARAT, or PFAS), an enzyme in the cellular purine biosynthesis, are important for disrupting the intrinsic antiviral response associated with Promyelocytic Leukemia (PML) protein-associated nuclear bodies (PML-NBs) by proteasome-dependent and independent mechanisms. In addition, all herpesviruses encode for a potent ubiquitin protease that can efficiently remove ubiquitin chains from proteins and thereby interfere with several different cellular pathways. In this review, we discuss mechanisms and functional consequences of virus-induced ubiquitination and deubiquitination for early events in gammaherpesviral infection. Full article
(This article belongs to the Special Issue Viruses, ERAD, and the Proteasome)
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694 KiB  
Review
Arms Race between Enveloped Viruses and the Host ERAD Machinery
by Dylan A. Frabutt and Yong-Hui Zheng
Viruses 2016, 8(9), 255; https://doi.org/10.3390/v8090255 - 19 Sep 2016
Cited by 22 | Viewed by 7863
Abstract
Enveloped viruses represent a significant category of pathogens that cause serious diseases in animals. These viruses express envelope glycoproteins that are singularly important during the infection of host cells by mediating fusion between the viral envelope and host cell membranes. Despite low homology [...] Read more.
Enveloped viruses represent a significant category of pathogens that cause serious diseases in animals. These viruses express envelope glycoproteins that are singularly important during the infection of host cells by mediating fusion between the viral envelope and host cell membranes. Despite low homology at protein levels, three classes of viral fusion proteins have, as of yet, been identified based on structural similarities. Their incorporation into viral particles is dependent upon their proper sub-cellular localization after being expressed and folded properly in the endoplasmic reticulum (ER). However, viral protein expression can cause stress in the ER, and host cells respond to alleviate the ER stress in the form of the unfolded protein response (UPR); the effects of which have been observed to potentiate or inhibit viral infection. One important arm of UPR is to elevate the capacity of the ER-associated protein degradation (ERAD) pathway, which is comprised of host quality control machinery that ensures proper protein folding. In this review, we provide relevant details regarding viral envelope glycoproteins, UPR, ERAD, and their interactions in host cells. Full article
(This article belongs to the Special Issue Viruses, ERAD, and the Proteasome)
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2096 KiB  
Review
How Polyomaviruses Exploit the ERAD Machinery to Cause Infection
by Allison Dupzyk and Billy Tsai
Viruses 2016, 8(9), 242; https://doi.org/10.3390/v8090242 - 29 Aug 2016
Cited by 30 | Viewed by 6978
Abstract
To infect cells, polyomavirus (PyV) traffics from the cell surface to the endoplasmic reticulum (ER) where it hijacks elements of the ER-associated degradation (ERAD) machinery to penetrate the ER membrane and reach the cytosol. From the cytosol, the virus transports to the nucleus, [...] Read more.
To infect cells, polyomavirus (PyV) traffics from the cell surface to the endoplasmic reticulum (ER) where it hijacks elements of the ER-associated degradation (ERAD) machinery to penetrate the ER membrane and reach the cytosol. From the cytosol, the virus transports to the nucleus, enabling transcription and replication of the viral genome that leads to lytic infection or cellular transformation. How PyV exploits the ERAD machinery to cross the ER membrane and access the cytosol, a decisive infection step, remains enigmatic. However, recent studies have slowly unraveled many aspects of this process. These emerging insights should advance our efforts to develop more effective therapies against PyV-induced human diseases. Full article
(This article belongs to the Special Issue Viruses, ERAD, and the Proteasome)
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