The asymmetrical distribution of the cellular organelles inside the cell is maintained by a group of cell polarity proteins. The maintenance of polarity is one of the vital host defense mechanisms against pathogens, and the loss of it contributes to infection facilitation and cancer progression. Studies have suggested that infection of viruses and bacteria alters cell polarity. Helicobacter pylori and Epstein-Barr virus are group I carcinogens involved in the progression of multiple clinical conditions besides gastric cancer (GC) and Burkitt's lymphoma, respectively. Moreover, the coinfection of both these pathogens contributes to a highly aggressive form of GC. H. pylori and EBV target the host cell polarity complexes for their pathogenesis. H. pylori-associated proteins like CagA, VacA OipA, and urease were shown to imbalance the cellular homeostasis by altering the cell polarity. Similarly, EBV-associated genes LMP1, LMP2A, LMP2B, EBNA3C, and EBNA1 also contribute to altered cell asymmetry. This review summarized all the possible mechanisms involved in cell polarity deformation in H. pylori and EBV-infected epithelial cells. We have also discussed deregulated molecular pathways like NF-κB, TGF-β/SMAD, and β-catenin in H. pylori, EBV, and their coinfection that further modulate PAR, SCRIB, or CRB polarity complexes in epithelial cells.

• MeSH
• Helicobacter pylori * genetika   MeSH
• infekce virem Epsteina-Barrové * mikrobiologie   patologie   MeSH
• infekce vyvolané Helicobacter pylori * mikrobiologie   MeSH
• koinfekce * mikrobiologie   MeSH
• lidé MeSH
• nádory žaludku * genetika   mikrobiologie   patologie   MeSH
• polarita buněk MeSH
• virové proteiny MeSH
• virus Epsteinův-Barrové genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Protein aggregates and abnormal proteins are toxic and associated with neurodegenerative diseases. There are several mechanisms to help cells get rid of aggregates but little is known on how cells prevent aggregate-prone proteins from being synthesised. The EBNA1 of the Epstein-Barr virus (EBV) evades the immune system by suppressing its own mRNA translation initiation in order to minimize the production of antigenic peptides for the major histocompatibility (MHC) class I pathway. Here we show that the emerging peptide of the disordered glycine-alanine repeat (GAr) within EBNA1 dislodges the nascent polypeptide-associated complex (NAC) from the ribosome. This results in the recruitment of nucleolin to the GAr-encoding mRNA and suppression of mRNA translation initiation in cis. Suppressing NAC alpha (NACA) expression prevents nucleolin from binding to the GAr mRNA and overcomes GAr-mediated translation inhibition. Taken together, these observations suggest that EBNA1 exploits a nascent protein quality control pathway to regulate its own rate of synthesis that is based on sensing the nascent GAr peptide by NAC followed by the recruitment of nucleolin to the GAr-encoding RNA sequence.

• MeSH
• alanin MeSH
• fosfoproteiny MeSH
• glycin MeSH
• infekce virem Epsteina-Barrové * MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• peptidy genetika   MeSH
• proteinové agregáty MeSH
• proteiny vázající RNA metabolismus   MeSH
• virus Epsteinův-Barrové - jaderné antigeny metabolismus   MeSH
• virus Epsteinův-Barrové * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Human herpesviruses (HHVs) are large DNA viruses with highly infectious characteristics. HHVs can induce lytic and latent infections in their host, and most of these viruses are neurotropic, with the capacity to generate severe and chronic neurological diseases of the peripheral nervous system (PNS) and central nervous system (CNS). Treatment of HHV infections based on strategies that include natural products-derived drugs is one of the most rapidly developing fields of modern medicine. Therefore, in this paper, we lend insights into the recent advances that have been achieved during the past five years in utilizing flavonoids as promising natural drugs for the treatment of HHVs infections of the nervous system such as alpha-herpesviruses (herpes simplex virus type 1, type 2, and varicella-zoster virus), beta-herpesviruses (human cytomegalovirus), and gamma-herpesviruses (Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus). The neurological complications associated with infections induced by the reviewed herpesviruses are emphasized. Additionally, this work covers all possible mechanisms and pathways by which flavonoids induce promising therapeutic actions against the above-mentioned herpesviruses.

• MeSH
• centrální nervový systém MeSH
• flavonoidy farmakologie   terapeutické užití   MeSH
• herpetické infekce * farmakoterapie   MeSH
• infekce virem Epsteina-Barrové * MeSH
• lidé MeSH
• lidský herpesvirus 1 * genetika   MeSH
• virus Epsteinův-Barrové genetika   MeSH
• virus varicella zoster genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The oncogenic Epstein-Barr virus (EBV) evades the immune system but has an Achilles heel: its genome maintenance protein EBNA1. Indeed, EBNA1 is essential for viral genome maintenance but is also highly antigenic. Hence, EBV seemingly evolved a system in which the glycine-alanine repeat (GAr) of EBNA1 limits the translation of its own mRNA to the minimal level to ensure its essential function, thereby, at the same time, minimizing immune recognition. Therefore, defining intervention points at which to interfere with GAr-based inhibition of translation is an important step to trigger an immune response against EBV-carrying cancers. The host protein nucleolin (NCL) plays a critical role in this process via a direct interaction with G-quadruplexes (G4) formed in the GAr-encoding sequence of the viral EBNA1 mRNA. Here we show that the C-terminal arginine-glycine-rich (RGG) motif of NCL is crucial for its role in GAr-based inhibition of translation by mediating interaction of NCL with G4 of EBNA1 mRNA. We also show that this interaction depends on the type I arginine methyltransferase family, notably PRMT1 and PRMT3: drugs or small interfering RNA that target these enzymes prevent efficient binding of NCL on G4 of EBNA1 mRNA and relieve GAr-based inhibition of translation and of antigen presentation. Hence, this work defines type I arginine methyltransferases as therapeutic targets to interfere with EBNA1 and EBV immune evasion.

• MeSH
• imunitní systém metabolismus   MeSH
• infekce onkogenními viry * farmakoterapie   metabolismus   MeSH
• infekce virem Epsteina-Barrové * genetika   MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• onkogenní viry genetika   metabolismus   MeSH
• proteinarginin-N-methyltransferasy MeSH
• represorové proteiny MeSH
• virus Epsteinův-Barrové - jaderné antigeny genetika   metabolismus   MeSH
• virus Epsteinův-Barrové * genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cíl: Ateroskleróza je hlavním etiologickým faktorem v rozvoji ischemické choroby srdeční, postižení karotických tepen i ischemické choroby dolních končetin. V naší studii jsme se pokusili prokázat přítomnost a účinek viru Epsteina-Barrové (Epstein-Barr virus, EBV) na stenózu karotických tepen vedoucí k rozvoji chronického zánětu s tvorbou prozánětlivých cytokinů a vyvolávající aterosklerózu. Materiál a metody: V období mezi dubnem 2017 a dubnem 2018 bylo na klinice kardiochirurgie lékařské fakulty istanbulské univerzity po podepsání informovaného souhlasu do této studie zařazeno 36 pacientů po endarterektomii karotid. U každého pacienta (dobrovolníka) byly zaznamenány věk, pohlaví, tělesná výška a hmotnost. Ve skupině těchto pacientů bylo 58,3 % (n = 21) mužů a 41,7 % (n = 15) žen. Byly zaznamenány i komorbidity jako hypertenze a diabetes mellitus. Výsledky: Nebyl nalezen významný rozdíl v pozitivitě na EBV (DNA) na základě přítomnosti hyperlipidemie, pohlaví a věku. Pozitivita na EBV (DNA) však byla nicméně vyšší (i když ne statisticky významně) u pacientů s komorbiditami, jako jsou hypertenze a diabetes mellitus. Pozitivita na EBV (DNA) byla zjištěna u 42,1 % pacientů s oboustrannou stenózou karotických tepen a nulová u pacientů bez oboustranné stenózy karotických tepen (p = 0,002). Pozitivita na EBV (DNA) byla statisticky významně vyšší u pacientů s oboustrannou stenózou karotických tepen. Závěr: Domníváme se, že statisticky významně vyšší hodnoty pozitivity na EBV (DNA) u pacientů s oboustrannou stenózou karotických tepen by měly podnítit další výzkum v oblasti vlivu virové etiologie na rozvoj aterosklerózy; to si však vyžádá další studie.

Objective: Atherosclerosis is the mainly etiologic factor of coronary artery disease, carotid artery disease and peripheral artery disease. In our study, we aimed to show the presence and effect of Epstein-Barr virus (EBV) on the carotid artery stenosis leading chronic inflammatory process by producing pro-inflammatory cytokines and causing atherosclerosis. Material and methods: Between April 2017 and April 2018, thirty-six patients, who underwent carotid endarterectomy at Department of Cardiovascular Surgery, Istanbul University Istanbul Medical Faculty, are included in this study upon their consent. Each voluntary patient was initially recorded for age, sex, height and weight. Among 36 patients included in the study, 58.3% (n = 21) were male and 41.7% (n = 15) were female. The comorbidities such as hypertension, diabetes mellitus were considered. Results: There was not significant difference in EBV (DNA) positivity according to hyperlipidemia presence, sex, and age factors. However, the EBV (DNA) positivity was higher in the patients with co-morbidities such as hypertension and diabetes mellitus; no significant difference was detected. EBV (DNA) positivity in patients with bilateral carotid artery stenosis was 42.1% and it was 0% in patients without bilateral carotid artery stenosis (p: 0,002). The EBV (DNA) positivity was significantly higher in patients with bilateral carotid artery stenosis Conclusion: We believe that our significantly high EBV (DNA) rates in the patients with bilateral carotid artery stenosis may encourage the studies that claim the role of viral etiology on atherosclerosis, however, further studies are needed.

• MeSH
• ateroskleróza etiologie   MeSH
• infekce virem Epsteina-Barrové * MeSH
• karotická endarterektomie MeSH
• komorbidita MeSH
• lidé MeSH
• rizikové faktory kardiovaskulárních chorob MeSH
• sekvenční analýza DNA MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stenóza arteria carotis * etiologie   MeSH
• virus Epsteinův-Barrové genetika   MeSH
• zánět MeSH
• Check Tag
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• klinická studie MeSH

The Epstein-Barr virus (EBV) immediate early transactivator Zta plays a key role in regulating the transition from latency to the lytic replication stages of EBV infection. Regulation of Zta is known to be controlled through a number of transcriptional and posttranscriptional events. Here, we show that Zta is targeted for ubiquitin modification and that this can occur in EBV-negative and in EBV-infected cells. Genetic studies show critical roles for both an amino-terminal region of Zta and the basic DNA binding domain of Zta in regulating Zta ubiquitination. Pulse-chase experiments demonstrate that the bulk population of Zta is relatively stable but that at least a subset of ubiquitinated Zta molecules are targeted for degradation in the cell. Mutation of four out of a total of nine lysine residues in Zta largely abrogates its ubiquitination, indicating that these are primary ubiquitination target sites. A Zta mutant carrying mutations at these four lysine residues (lysine 12, lysine 188, lysine 207, and lysine 219) cannot induce latently infected cells to produce and/or release infectious virions. Nevertheless, this mutant can induce early gene expression, suggesting a possible defect at the level of viral replication or later in the lytic cascade. As far as we know, this is the first study that has investigated the targeting of Zta by ubiquitination or its role in Zta function.IMPORTANCE Epstein-Barr virus (EBV) is a ubiquitous human pathogen and associated with various human diseases. EBV undergoes latency and lytic replication stages in its life cycle. The transition into the lytic replication stage, at which virus is produced, is mainly regulated by the viral gene product, Zta. Therefore, the regulation of Zta function becomes a central issue regarding viral biology and pathogenesis. Known modifications of Zta include phosphorylation and sumoylation. Here, we report the role of ubiquitination in regulating Zta function. We found that Zta is subjected to ubiquitination in both EBV-infected and EBV-negative cells. The ubiquitin modification targets 4 lysine residues on Zta, leading to both mono- and polyubiquitination of Zta. Ubiquitination of Zta affects the protein's stability and likely contributes to the progression of viral lytic replication. The function and fate of Zta may be determined by the specific lysine residue being modified.

• MeSH
• buněčné linie MeSH
• infekce virem Epsteina-Barrové virologie   MeSH
• lidé MeSH
• mutace MeSH
• promotorové oblasti (genetika) MeSH
• proteinové domény MeSH
• regulace exprese virových genů MeSH
• replikace viru MeSH
• trans-aktivátory genetika   metabolismus   MeSH
• ubikvitin metabolismus   MeSH
• vazba proteinů MeSH
• virové proteiny genetika   metabolismus   MeSH
• virus Epsteinův-Barrové genetika   fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Cell growth requires a high level of protein synthesis and oncogenic pathways stimulate cell proliferation and ribosome biogenesis. Less is known about how cells respond to dysfunctional mRNA translation and how this feeds back into growth regulatory pathways. The Epstein-Barr virus (EBV)-encoded EBNA1 causes mRNA translation stress in cis that activates PI3Kδ. This leads to the stabilization of MDM2, induces MDM2's binding to the E2F1 mRNA and promotes E2F1 translation. The MDM2 serine 166 regulates the interaction with the E2F1 mRNA and deletion of MDM2 C-terminal RING domain results in a constitutive E2F1 mRNA binding. Phosphorylation on serine 395 following DNA damage instead regulates p53 mRNA binding to its RING domain and prevents the E2F1 mRNA interaction. The p14Arf tumour suppressor binds MDM2 and in addition to preventing degradation of the p53 protein it also prevents the E2F1 mRNA interaction. The data illustrate how two MDM2 domains selectively bind specific mRNAs in response to cellular conditions to promote, or suppress, cell growth and how p14Arf coordinates MDM2's activity towards p53 and E2F1. The data also show how EBV via EBNA1-induced mRNA translation stress targets the E2F1 and the MDM2 - p53 pathway.

• MeSH
• buněčný cyklus genetika   MeSH
• fosforylace genetika   MeSH
• karcinogeneze genetika   MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• nádorový supresorový protein p14ARF genetika   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory genetika   virologie   MeSH
• onkogeny genetika   MeSH
• poškození DNA genetika   MeSH
• proliferace buněk genetika   MeSH
• proteinové domény genetika   MeSH
• protoonkogenní proteiny c-mdm2 genetika   MeSH
• RRM proteiny genetika   MeSH
• transkripční faktor E2F1 genetika   MeSH
• tumor supresorové geny MeSH
• virus Epsteinův-Barrové genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The Epstein-Barr virus (EBV) is found almost exclusively in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), yet its contribution to this tumour remains poorly understood. We have focused on the EBV-encoded latent membrane protein-1 (LMP1), a constitutively activated CD40 homologue expressed in almost all EBV-positive DLBCLs and which can disrupt germinal centre (GC) formation and drive lymphomagenesis in mice. Comparison of the transcriptional changes that follow LMP1 expression with those that follow transient CD40 signalling in human GC B cells enabled us to define pathogenic targets of LMP1 aberrantly expressed in ABC-DLBCL. These included the down-regulation of S1PR2, a sphingosine-1-phosphate (S1P) receptor that is transcriptionally down-regulated in ABC-DLBCL, and when genetically ablated leads to DLBCL in mice. Consistent with this, we found that LMP1-expressing primary ABC-DLBCLs were significantly more likely to lack S1PR2 expression than were LMP1-negative tumours. Furthermore, we showed that the down-regulation of S1PR2 by LMP1 drives a signalling loop leading to constitutive activation of the phosphatidylinositol-3-kinase (PI3-K) pathway. Finally, core LMP1-PI3-K targets were enriched for lymphoma-related transcription factors and genes associated with shorter overall survival in patients with ABC-DLBCL. Our data identify a novel function for LMP1 in aggressive DLBCL. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

• MeSH
• 1-fosfatidylinositol-3-kinasa metabolismus   MeSH
• antigeny CD40 genetika   metabolismus   MeSH
• databáze genetické MeSH
• difúzní velkobuněčný B-lymfom genetika   metabolismus   mortalita   virologie   MeSH
• infekce virem Epsteina-Barrové mortalita   virologie   MeSH
• interakce hostitele a patogenu MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• prognóza MeSH
• proteiny virové matrix genetika   metabolismus   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• receptory sfingosin-1-fosfátu genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• signální transdukce MeSH
• virová transformace buněk MeSH
• virus Epsteinův-Barrové genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The c-myc oncogene stimulates ribosomal biogenesis and protein synthesis to promote cellular growth. However, the pathway by which cells sense and restore dysfunctional mRNA translation and how this is linked to cell proliferation and growth is not known. We here show that mRNA translation stress in cis triggered by the gly-ala repeat sequence of Epstein-Barr virus (EBV)-encoded EBNA1, results in PI3Kδ-dependent induction of E2F1 mRNA translation with the consequent activation of c-Myc and cell proliferation. Treatment with a specific PI3Kδ inhibitor Idelalisib (CAL-101) suppresses E2F1 and c-Myc levels and causes cell death in EBNA1-induced B cell lymphomas. Suppression of PI3Kδ prevents E2F1 activation also in non-EBV-infected cells. These data illustrate an mRNA translation stress-response pathway for E2F1 activation that is exploited by EBV to promote cell growth and proliferation, offering new strategies to treat EBV-carrying cancers.

• MeSH
• buněčné linie MeSH
• fosfatidylinositol-3-kinasy třídy I genetika   metabolismus   MeSH
• interakce hostitele a patogenu genetika   MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory genetika   patologie   virologie   MeSH
• proliferace buněk genetika   MeSH
• proteosyntéza * MeSH
• regulace genové exprese u nádorů MeSH
• transkripční faktor E2F1 genetika   metabolismus   MeSH
• virus Epsteinův-Barrové - jaderné antigeny genetika   metabolismus   MeSH
• virus Epsteinův-Barrové genetika   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Squamous cell carcinoma of the head and neck (SCCHN) comprises a large group of cancers in the oral cavity and nasopharyngeal area that typically arise in older males in association with alcohol/tobacco usage. Within the oral cavity, the mobile tongue is the most common site for tumour development. The incidence of tongue squamous cell carcinoma (TSCC) is increasing in younger people, which has been suggested to associate with a viral aetiology. Two common human oncogenic viruses, human papilloma virus (HPV) and Epstein-Barr virus (EBV) are known causes of certain types of SCCHN, namely the oropharynx and nasopharynx, respectively. EBV infects most adults worldwide through oral transmission and establishes a latent infection, with sporadic productive viral replication and release of virus in the oral cavity throughout life. In view of the prevalence of EBV in the oral cavity and recent data indicating that it infects tongue epithelial cells and establishes latency, we examined 98 cases of primary squamous cell carcinoma of the mobile tongue and 15 cases of tonsillar squamous cell carcinoma for the presence of EBV-encoded RNAs (EBERs), EBV DNA and an EBV-encoded protein, EBNA-1. A commercially available in situ hybridisation kit targeting EBER transcripts (EBER-ISH) showed a positive signal in the cytoplasm and/or nuclei of tumour cells in 43% of TSCCs. However, application of control probes and RNase A digestion using in-house developed EBER-ISH showed identical EBER staining patterns, indicating non-specific signals. PCR analysis of the BamH1 W repeat sequences did not identify EBV genomes in tumour samples. Immunohistochemistry for EBNA-1 was also negative. These data exclude EBV as a potential player in TSCC in both old and young patients and highlight the importance of appropriate controls for EBER-ISH in investigating EBV in human diseases.

• MeSH
• DNA virů analýza   metabolismus   MeSH
• dospělí MeSH
• hybridizace in situ MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádory jazyka patologie   virologie   MeSH
• polymerázová řetězová reakce MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• spinocelulární karcinom patologie   virologie   MeSH
• tonzilární nádory patologie   virologie   MeSH
• virus Epsteinův-Barrové - jaderné antigeny genetika   metabolismus   MeSH
• virus Epsteinův-Barrové genetika   izolace a purifikace   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH