Special Issue "Viruses and the Unfolded Protein Response"

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

Deadline for manuscript submissions: closed (1 December 2019).

Special Issue Editors

Dr. Craig McCormick
E-Mail
Guest Editor
Department of Microbiology and Immunology, Dalhousie University, Sir Charles Tupper Medical Building, Room 7-P 5850 College Street, Halifax, Nova Scotia, Canada B3H 4R2
Interests: influenza A virus; Kaposi’s sarcoma-associated herpesvirus; viral oncogenes; mRNA turnover and translation; stress granules; p-bodies; autophagy; unfolded protein response; inflammation; host shutoff
Special Issues, Collections and Topics in MDPI journals
Dr. Carolina Arias
E-Mail Website
Guest Editor
University of California Santa Barbara
Interests: herpesviruses; zika virus; protein synthesis; unfolded protein response; RNA-seq; CRISPR
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Viruses use host cell translation machinery to synthesize viral proteins, and the endoplasmic reticulum (ER) to ensure proper folding, post-translational modification, and trafficking of transmembrane and secreted viral proteins. Overloading the ER’s folding capacity activates the unfolded protein response (UPR), whereby the ER stress sensors PERK, IRE1, and ATF6 initiate signals that transiently attenuate translation and stimulate the production of stress-mitigating transcription factors. UPR transcription increases production of ER protein folding machinery, expands the ER’s surface area, and increases degradation of misfolded proteins by ER-associated degradation (ERAD). The UPR also plays important roles in cell fate decisions and immune responses. At present, relatively little is known about how viruses manipulate the UPR and the functional consequences of these interactions.

For this Special Issue of Viruses, we hope to assemble a collection of research papers and reviews that provide a comprehensive view of this emerging field of virus research. Topics of interest include, but are not limited to:

  1. viral protein synthesis and interplay with the UPR and/or the integrated stress response;
  2. viral modulation of UPR sensors;
  3. viral modulation of UPR transcription;
  4. viral control of ERAD;
  5. effects of viral infection on UPR-dependent cell differentiation and cell fate;
  6. the UPR and viral pathogenesis; and
  7. therapeutic targeting of the UPR during viral infection.

We hope that this Special Issue will serve as a valuable resource to new and established researchers in the field, and frame important unanswered questions to focus future research efforts.

Dr. Craig McCormick
Dr. Carolina Arias
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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 2200 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

  • virus
  • protein
  • translation
  • endoplasmic reticulum
  • unfolded protein response
  • IRE1
  • XBP1
  • PERK
  • ATF6
  • ERAD
  • secretion

Published Papers (4 papers)

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Research

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Article
Hepatitis C Virus Proteins Core and NS5A Are Highly Sensitive to Oxidative Stress-Induced Degradation after eIF2α/ATF4 Pathway Activation
Viruses 2020, 12(4), 425; https://0-doi-org.brum.beds.ac.uk/10.3390/v12040425 - 09 Apr 2020
Cited by 3 | Viewed by 1053
Abstract
Hepatitis C virus (HCV) infection is accompanied by increased oxidative stress and endoplasmic reticulum stress as a consequence of viral replication, production of viral proteins, and pro-inflammatory signals. To overcome the cellular stress, hepatocytes have developed several adaptive mechanisms like anti-oxidant response, activation [...] Read more.
Hepatitis C virus (HCV) infection is accompanied by increased oxidative stress and endoplasmic reticulum stress as a consequence of viral replication, production of viral proteins, and pro-inflammatory signals. To overcome the cellular stress, hepatocytes have developed several adaptive mechanisms like anti-oxidant response, activation of Unfolded Protein Response and autophagy to achieve cell survival. These adaptive mechanisms could both improve or inhibit viral replication, however, little is known in this regard. In this study, we investigate the mechanisms by which hepatocyte-like (Huh7) cells adapt to cellular stress in the context of HCV protein overexpression and oxidative stress. Huh7 cells stably expressing individual HCV (Core, NS3/4A and NS5A) proteins were treated with the superoxide anion donor menadione to induce oxidative stress. Production of reactive oxygen species and activation of caspase 3 were quantified. The activation of the eIF2α/ATF4 pathway and changes in the steady state levels of the autophagy-related proteins LC3 and p62 were determined either by quantitative polymerase chain reaction (qPCR) or Western blotting. Huh7 cells expressing Core or NS5A demonstrated reduced oxidative stress and apoptosis. In addition, phosphorylation of eIF2α and increased ATF4 and CHOP expression was observed with subsequent HCV Core and NS5A protein degradation. In line with these results, in liver biopsies from patients with hepatitis C, the expression of ATF4 and CHOP was confirmed. HCV Core and NS5A protein degradation was reversed by antioxidant treatment or silencing of the autophagy adaptor protein p62. We demonstrated that hepatocyte-like cells expressing HCV proteins and additionally exposed to oxidative stress adapt to cellular stress through eIF2a/ATF4 activation and selective degradation of HCV pro-oxidant proteins Core and NS5A. This selective degradation is dependent on p62 and results in increased resistance to apoptotic cell death induced by oxidative stress. This mechanism may provide a new key for the study of HCV pathology and lead to novel clinically applicable therapeutic interventions. Full article
(This article belongs to the Special Issue Viruses and the Unfolded Protein Response)
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Article
IRE1α Promotes Zika Virus Infection via XBP1
Viruses 2020, 12(3), 278; https://0-doi-org.brum.beds.ac.uk/10.3390/v12030278 - 03 Mar 2020
Cited by 7 | Viewed by 1702
Abstract
Zika virus (ZIKV) is an emergent member of the Flaviviridae family which causes severe congenital defects and other major sequelae, but the cellular processes that support ZIKV replication are incompletely understood. Related flaviviruses use the endoplasmic reticulum (ER) as a membranous platform for [...] Read more.
Zika virus (ZIKV) is an emergent member of the Flaviviridae family which causes severe congenital defects and other major sequelae, but the cellular processes that support ZIKV replication are incompletely understood. Related flaviviruses use the endoplasmic reticulum (ER) as a membranous platform for viral replication and induce ER stress during infection. Our data suggest that ZIKV activates IRE1α, a component of the cellular response to ER stress. IRE1α is an ER-resident transmembrane protein that possesses a cytosolic RNase domain. Upon activation, IRE1α initiates nonconventional cytoplasmic splicing of XBP1 mRNA. Spliced XBP1 encodes a transcription factor, which upregulates ER-related targets. We find that ZIKV infection induces XBP1 mRNA splicing and induction of XBP1 target genes. Small molecule inhibitors of IRE1α, including those specific for the nuclease function, prevent ZIKV-induced cytotoxicity, as does genetic disruption of IRE1α. Optimal ZIKV RNA replication requires both IRE1α and XBP1. Spliced XBP1 has been described to cause ER expansion and remodeling and we find that ER redistribution during ZIKV infection requires IRE1α nuclease activity. Finally, we demonstrate that inducible genetic disruption of IRE1α and XBP1 impairs ZIKV replication in a mouse model of infection. Together, our data indicate that the ER stress response component IRE1α promotes ZIKV infection via XBP1 and may represent a potential therapeutic target. Full article
(This article belongs to the Special Issue Viruses and the Unfolded Protein Response)
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Article
The Porcine Deltacoronavirus Replication Organelle Comprises Double-Membrane Vesicles and Zippered Endoplasmic Reticulum with Double-Membrane Spherules
Viruses 2019, 11(11), 1030; https://0-doi-org.brum.beds.ac.uk/10.3390/v11111030 - 05 Nov 2019
Cited by 15 | Viewed by 2024
Abstract
Porcine deltacoronavirus (PDCoV) was first identified in Hong Kong in 2012 from samples taken from pigs in 2009. PDCoV was subsequently identified in the USA in 2014 in pigs with a history of severe diarrhea. The virus has now been detected in pigs [...] Read more.
Porcine deltacoronavirus (PDCoV) was first identified in Hong Kong in 2012 from samples taken from pigs in 2009. PDCoV was subsequently identified in the USA in 2014 in pigs with a history of severe diarrhea. The virus has now been detected in pigs in several countries around the world. Following the development of tissue culture adapted strains of PDCoV, it is now possible to address questions regarding virus–host cell interactions for this genera of coronavirus. Here, we presented a detailed study of PDCoV-induced replication organelles. All positive-strand RNA viruses induce the rearrangement of cellular membranes during virus replication to support viral RNA synthesis, forming the replication organelle. Replication organelles for the Alpha-, Beta-, and Gammacoronavirus genera have been characterized. All coronavirus genera induced the formation of double-membrane vesicles (DMVs). In addition, Alpha- and Betacoronaviruses induce the formation of convoluted membranes, while Gammacoronaviruses induce the formation of zippered endoplasmic reticulum (ER) with tethered double-membrane spherules. However, the structures induced by Deltacoronaviruses, particularly the presence of convoluted membranes or double-membrane spherules, are unknown. Initially, the dynamics of PDCoV strain OH-FD22 replication were assessed with the onset of viral RNA synthesis, protein synthesis, and progeny particle release determined. Subsequently, virus-induced membrane rearrangements were identified in infected cells by electron microscopy. As has been observed for all other coronaviruses studied to date, PDCoV replication was found to induce the formation of double-membrane vesicles. Significantly, however, PDCoV replication was also found to induce the formation of regions of zippered endoplasmic reticulum, small associated tethered vesicles, and double-membrane spherules. These structures strongly resemble the replication organelle induced by avian Gammacoronavirus infectious bronchitis virus. Full article
(This article belongs to the Special Issue Viruses and the Unfolded Protein Response)
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Review

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Review
Herpesviruses and the Unfolded Protein Response
Viruses 2020, 12(1), 17; https://0-doi-org.brum.beds.ac.uk/10.3390/v12010017 - 21 Dec 2019
Cited by 19 | Viewed by 3246
Abstract
Herpesviruses usurp cellular stress responses to promote viral replication and avoid immune surveillance. The unfolded protein response (UPR) is a conserved stress response that is activated when the protein load in the ER exceeds folding capacity and misfolded proteins accumulate. The UPR aims [...] Read more.
Herpesviruses usurp cellular stress responses to promote viral replication and avoid immune surveillance. The unfolded protein response (UPR) is a conserved stress response that is activated when the protein load in the ER exceeds folding capacity and misfolded proteins accumulate. The UPR aims to restore protein homeostasis through translational and transcriptional reprogramming; if homeostasis cannot be restored, the UPR switches from “helper” to “executioner”, triggering apoptosis. It is thought that the burst of herpesvirus glycoprotein synthesis during lytic replication causes ER stress, and that these viruses may have evolved mechanisms to manage UPR signaling to create an optimal niche for replication. The past decade has seen considerable progress in understanding how herpesviruses reprogram the UPR. Here we provide an overview of the molecular events of UPR activation, signaling and transcriptional outputs, and highlight key evidence that herpesviruses hijack the UPR to aid infection. Full article
(This article belongs to the Special Issue Viruses and the Unfolded Protein Response)
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