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10 pages, 1571 KiB

Open AccessEditor’s ChoiceArticle

RNR-R2 Upregulation by a Short Non-Coding Viral Transcript

by Karin Broennimann, Inna Ricardo-Lax, Julia Adler, Eleftherios Michailidis, Ype P. de Jong, Nina Reuven and Yosef Shaul

Biomolecules 2021, 11(12), 1822; https://doi.org/10.3390/biom11121822 - 3 Dec 2021

Cited by 2 | Viewed by 2744

Abstract

DNA viruses require dNTPs for replication and have developed different strategies to increase intracellular dNTP pools. Hepatitis B virus (HBV) infects non-dividing cells in which dNTPs are scarce and the question is how viral replication takes place. Previously we reported that the virus induces the DNA damage response (DDR) pathway culminating in RNR-R2 expression and the generation of an active RNR holoenzyme, the key regulator of dNTP levels, leading to an increase in dNTPs. How the virus induces DDR and RNR-R2 upregulation is not completely known. The viral HBx open reading frame (ORF) was believed to trigger this pathway. Unexpectedly, however, we report here that the production of HBx protein is dispensable. We found that a small conserved region of 125 bases within the HBx ORF is sufficient to upregulate RNR-R2 expression in growth-arrested HepG2 cells and primary human hepatocytes. The observed HBV mRNA embedded regulatory element is named ERE. ERE in isolation is sufficient to activate the ATR-Chk1-E2F1-RNR-R2 DDR pathway. These findings demonstrate a non-coding function of HBV transcripts to support its propagation in non-cycling cells. Full article

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18 pages, 5160 KiB

Open AccessArticle

Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth

by Nnenna Nwogu, Luz E. Ortiz and Hyun Jin Kwun

Viruses 2020, 12(9), 1043; https://doi.org/10.3390/v12091043 - 18 Sep 2020

Cited by 10 | Viewed by 4699

Abstract

Merkel cell polyomavirus (MCV) is the only known human oncogenic virus in the polyomaviridae family and the etiological agent of most Merkel cell carcinomas (MCC). MCC is an aggressive and highly metastatic skin cancer with a propensity for recurrence and poor prognosis. Large tumor antigen (LT), is an essential oncoprotein for MCV transcription, viral replication, and cancer cell proliferation. MCV LT is a short-lived protein that encodes a unique domain: MCV LT unique regions (MURs). These domains consist of phosphorylation sites that interact with multiple E3 ligases, thus limiting LT expression and consequently, viral replication. In this study, we show that MURs are necessary for regulating LT stability via multiple E3 ligase interactions, resulting in cell growth arrest. While expression of wild-type MCV LT induced a decrease in cellular proliferation, deletion of the MUR domains resulted in increased LT stability and cell proliferation. Conversely, addition of MURs to SV40 LT propagated E3 ligase interactions, which in turn, reduced SV40 LT stability and decreased cell growth activity. Our results demonstrate that compared to other human polyomaviruses (HPyVs), MCV LT has evolved to acquire the MUR domains that are essential for MCV LT autoregulation, potentially leading to viral latency and MCC. Full article

(This article belongs to the Special Issue Polyomaviruses)

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15 pages, 932 KiB

Open AccessEditor’s ChoiceReview

The Role of Apoptin in Chicken Anemia Virus Replication

by Cynthia Feng, Yingke Liang and Jose G. Teodoro

Pathogens 2020, 9(4), 294; https://doi.org/10.3390/pathogens9040294 - 16 Apr 2020

Cited by 16 | Viewed by 5371

Abstract

Apoptin is the Vp3 protein of chicken anemia virus (CAV), which infects the thymocytes and erythroblasts in young chickens, causing chicken infectious anemia and immunosuppression. Apoptin is highly studied for its ability to selectively induce apoptosis in human tumor cells and, thus, is a protein of interest in anti-tumor therapy. CAV apoptin is known to localize to different subcellular compartments in transformed and non-transformed cells, depending on the DNA damage response, and the phosphorylation of several identified threonine residues. In addition, apoptin interacts with molecular machinery such as the anaphase promoting complex/cyclosome (APC/C) to inhibit the cell cycle and induce arrest in G2/M phase. While these functions of apoptin contribute to the tumor-selective effect of the protein, they also provide an important fundamental framework to apoptin’s role in viral infection, pathogenesis, and propagation. Here, we reviewed how the regulation, localization, and functions of apoptin contribute to the viral life cycle and postulated its importance in efficient replication of CAV. A model of the molecular biology of infection is critical to informing our understanding of CAV and other related animal viruses that threaten the agricultural industry. Full article

(This article belongs to the Special Issue Chicken Anaemia Virus Infection)

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16 pages, 2708 KiB

Open AccessArticle

Characterizing Cellular Responses During Oncolytic Maraba Virus Infection

by Golnoush Hassanzadeh, Thet Naing, Tyson Graber, Seyed Mehdi Jafarnejad, David F. Stojdl, Tommy Alain and Martin Holcik

Int. J. Mol. Sci. 2019, 20(3), 580; https://doi.org/10.3390/ijms20030580 - 29 Jan 2019

Cited by 10 | Viewed by 5736

Abstract

The rising demand for powerful oncolytic virotherapy agents has led to the identification of Maraba virus, one of the most potent oncolytic viruses from Rhabdoviridae family which displays high selectivity for killing malignant cells and low cytotoxicity in normal cells. Although the virus is readied to be used for clinical trials, the interactions between the virus and the host cells is still unclear. Using a newly developed interferon-sensitive mutant Maraba virus (MG1), we have identified two key regulators of global translation (4E-BP1 and eIF2α) as being involved in the regulation of protein synthesis in the infected cells. Despite the translational arrest upon viral stress, we showed an up-regulation of anti-apoptotic Bcl-xL protein that provides a survival benefit for the host cell, yet facilitates effective viral propagation. Given the fact that eIF5B canonically regulates 60S ribosome subunit end joining and is able to replace the role of eIF2 in delivering initiator tRNA to the 40S ribosome subunit upon the phosphorylation of eIF2α we have tested whether eIF5B mediates the translation of target mRNAs during MG1 infection. Our results show that the inhibition of eIF5B significantly down-regulates the level of Bcl-xL steady-state mRNA, thus indirectly attenuates viral propagation. Full article

(This article belongs to the Special Issue Translational Control)

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24 pages, 6763 KiB

Open AccessArticle

Novel Uridine Glycoconjugates, Derivatives of 4-Aminophenyl 1-Thioglycosides, as Potential Antiviral Compounds

by Ewelina Krol, Gabriela Pastuch-Gawolek, Binay Chaubey, Gabriela Brzuska, Karol Erfurt and Boguslaw Szewczyk

Molecules 2018, 23(6), 1435; https://doi.org/10.3390/molecules23061435 - 13 Jun 2018

Cited by 3 | Viewed by 4550

Abstract

A novel series of uridine glycoconjugates, derivatives of 4-aminophenyl 1-thioglycosides, was designed and synthesized. All compounds were evaluated in vitro for their antiviral activity against hepatitis C virus (HCV) and classical swine fever virus (CSFV), two important human and animal viral pathogens for which new or improved therapeutic options are needed. The antiviral activity of all synthesized compounds was confirmed using pseudo-plaque reduction assays in which a significant arrest of CSFV and HCV growth was observed in the presence of these compounds. Two of the synthesized compounds, 9 and 12, displayed a significant inhibitory effect on HCV and CSFV propagation with IC₅₀ values of 4.9 and 13.5 µM for HCV and 4.2 and 4 µM for CSFV, respectively, with low cytotoxicity. Using various infection and replication models, we have shown that both compounds were able to significantly reduce viral genome replication by up to 90% with IC₅₀ values in the low micromolar range. A structure activity analysis of the synthesized compounds showed that the high antiviral activity was attributed to the hydrophobicity of glycoconjugates and the introduction of elements capable to coordinate metal ions into the spacer connecting the sugar and uridine moiety, which can be useful in the development of new antiviral compounds in the future. Full article

(This article belongs to the Collection Advances in Glycosciences)

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15 pages, 1103 KiB

Open AccessArticle

Arrest of Viral Proliferation by Ectopic Copies of Its Cognate Replication Origin

by Manuel S. Valenzuela and Chakradhari Sharan

Genes 2015, 6(2), 436-450; https://doi.org/10.3390/genes6020436 - 23 Jun 2015

Viewed by 5120

Abstract

The initiation step of DNA replication is the crucial determinant of proliferation in all organisms. This step depends on the specific interaction of DNA sequences present at origins of DNA replication and their cognate activators. We wished to explore the hypothesis that the presence of ectopic origin copies may interfere with proper genome duplication. Bacteriophage λ was used as a model system. To this end, the outcome of an infection of an E. coli strain harboring ectopic copies of the λ origin region was analyzed. By measuring the effect on the host growth, viral production, and electro-microscopic visualization of the resulting λ replicative intermediates, we concluded that the ectopic copies had prevented the normal initiation step of λ DNA replication. These results suggest that DNA decoys encoding viral origins could constitute effective tools to specifically arrest viral proliferation. Full article

(This article belongs to the Special Issue DNA Replication)

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