scholarly journals Identification of Three gp350/220 Regions Involved in Epstein-Barr Virus Invasion of Host Cells

2005 ◽  
Vol 280 (42) ◽  
pp. 35598-35605 ◽  
Author(s):  
Mauricio Urquiza ◽  
Ramses Lopez ◽  
Helena Patiño ◽  
Jaiver E. Rosas ◽  
Manuel E. Patarroyo
Keyword(s):  
Epstein Barr Virus ◽  
Host Cells ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals Interferon Antagonism of Epstein–Barr Virus Tegument Proteins

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 74
Author(s):  
Wai-Yan Lui ◽  
Sonia Jangra ◽  
Kit-San Yuen ◽  
Michael George Botelho ◽  
Dong-Yan Jin
Keyword(s):  
Epstein Barr Virus ◽  
Tyrosine Phosphatase ◽  
Host Cells ◽  
Tegument Protein ◽  
Small Subset ◽  
Type I ◽  
Type I Ifn ◽  
Tegument Proteins ◽  
Barr Virus ◽  
Epstein Barr

The Epstein–Barr virus (EBV) successfully infects 95% of all adults but causes Burkitt’s lymphoma, Hodgkin’s lymphoma, gastric carcinoma, nasopharyngeal carcinoma or other malignancies in only a small subset of infected individuals. The virus must have developed effective viral countermeasures to evade host innate immunity. In this study, we performed functional screens to identify EBV-encoded interferon (IFN) antagonists. Several tegument proteins were found to be potent suppressors of IFN production and/or signaling. The large tegument protein and deubiquitinase BPLF1 antagonized type I IFN production induced by DNA sensors cGAS and STING or RNA sensors RIG-I and MAVS. BPLF1’s ability to suppress innate immune signaling required its deubiquitinase activity. BPLF1 functioned as a catalytically active deubiquitinase for both K63- and K48-linked ubiquitin chains on STING and TBK1, with no ubiquitin linkage specificity. Induced expression of BPLF1 in EBV-infected cells through CRISPRa led to effective suppression of innate DNA and RNA sensing. Another EBV tegument protein, BGLF2, was found to suppress JAK-STAT signaling. This suppression was ascribed to more pronounced K48-linked polyubiquitination and proteasomal degradation of BGLF2-associated STAT2. In addition, BGLF2 also recruited tyrosine phosphatase SHP1 to inhibit tyrosine phosphorylation of JAK1 and STAT1. A BGLF2-deficient EBV activated type I IFN signaling more robustly. Taken together, we characterized the IFN antagonism of EBV tegument proteins BPLF1 and BGLF2, which modulate ubiquitination of key transducer proteins to counteract type I IFN production and signaling in host cells. Supported by HMRF 17160822, HMRF 18170942, and RGC C7027-16G.

scholarly journals Elucidation of the c-Jun N-Terminal Kinase Pathway Mediated by Epstein-Barr Virus-Encoded Latent Membrane Protein 1

2004 ◽  
Vol 24 (1) ◽  
pp. 192-199 ◽  
Author(s):  
Jun Wan ◽  
Luguo Sun ◽  
Jennifer Woo Mendoza ◽  
Yiu Loon Chui ◽  
Dolly P. Huang ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Epstein Barr Virus ◽  
Cellular Transformation ◽  
Latent Membrane Protein ◽  
Host Cells ◽  
Latent Membrane Protein 1 ◽  
Tnf Receptor ◽  
Jnk Pathway ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) is associated with several human diseases including infectious mononucleosis and nasopharyngeal carcinoma. EBV-encoded latent membrane protein 1 (LMP1) is oncogenic and indispensable for cellular transformation caused by EBV. Expression of LMP1 in host cells constitutively activates both the c-Jun N-terminal kinase (JNK) and NF-κB pathways, which contributes to the oncogenic effect of LMP1. However, the underlying signaling mechanisms are not very well understood. Based mainly on overexpression studies with various dominant-negative constructs, LMP1 was generally thought to functionally mimic members of the tumor necrosis factor (TNF) receptor superfamily in signaling. In contrast to the prevailing paradigm, using embryonic fibroblasts from different knockout mice and the small interfering RNA technique, we find that the LMP1-mediated JNK pathway is distinct from those mediated by either TNF-α or interleukin-1. Moreover, we have further elucidated the LMP1-mediated JNK pathway by demonstrating that LMP1 selectively utilizes TNF receptor-associated factor 6, TAK1/TAB1, and c-Jun N-terminal kinase kinases 1 and 2 to activate JNK.

scholarly journals Modulation of Epstein-Barr Virus Glycoprotein B (gB) Fusion Activity by the gB Cytoplasmic Tail Domain

mBio ◽  
2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Nicholas J. Garcia ◽  
Jia Chen ◽  
Richard Longnecker
Keyword(s):  
Membrane Fusion ◽  
Epstein Barr Virus ◽  
Cytoplasmic Tail ◽  
Host Cells ◽  
Glycoprotein B ◽  
Tail Domain ◽  
Induced Membrane ◽  
Barr Virus ◽  
Cellular Expression ◽  
Epstein Barr

ABSTRACTEpstein-Barr virus (EBV), along with other members of the herpesvirus family, requires a set of viral glycoproteins to mediate host cell attachment and entry. Viral glycoprotein B (gB), a highly conserved glycoprotein within the herpesvirus family, is thought to be the viral fusogen based on structural comparison of EBV gB and herpes simplex virus (HSV) gB with the postfusion crystal structure of vesicular stomatitis virus fusion protein glycoprotein G (VSV-G). In addition, mutational studies indicate that gB plays an important role in fusion function. In the current study, we constructed a comprehensive library of mutants with truncations of the C-terminal cytoplasmic tail domain (CTD) of EBV gB. Our studies indicate that the gB CTD is important in the cellular localization, expression, and fusion function of EBV gB. However, in line with observations from other studies, we conclude that the degree of cell surface expression of gB is not directly proportional to observed fusion phenotypes. Rather, we conclude that other biochemical or biophysical properties of EBV gB must be altered to explain the different fusion phenotypes observed.IMPORTANCEEpstein-Barr virus (EBV), like all enveloped viruses, fuses the virion envelope to a cellular membrane to allow release of the capsid, resulting in virus infection. To further characterize the function of EBV glycoprotein B (gB) in fusion, a comprehensive library of mutants with truncations in the gB C-terminal cytoplasmic tail domain (CTD) were made. These studies indicate that the CTD of gB is important for the cellular expression and localization of gB, as well as for the function of gB in fusion. These studies will lead to a better understanding of the mechanism of EBV-induced membrane fusion and herpesvirus-induced membrane fusion in general, which will ultimately lead to focused therapies guided at preventing viral entry into host cells.

scholarly journals Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by InhibitingBAD-Mediatedcaspase-3-Dependent Apoptosis

2015 ◽  
Vol 90 (3) ◽  
pp. 1359-1368 ◽  
Author(s):  
Hyoji Kim ◽  
Hoyun Choi ◽  
Suk Kyeong Lee
Keyword(s):  
Epstein Barr Virus ◽  
Caspase 3 ◽  
Immune Surveillance ◽  
Virus Production ◽  
Lytic Cycle ◽  
Host Cells ◽  
Immediate Early ◽  
Progeny Virus ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACTEpstein-Barr virus (EBV) is a human gammaherpesvirus associated with a variety of tumor types. EBV can establish latency or undergo lytic replication in host cells. In general, EBV remains latent in tumors and expresses a limited repertoire of latent proteins to avoid host immune surveillance. When the lytic cycle is triggered by some as-yet-unknown form of stimulation, lytic gene expression and progeny virus production commence. Thus far, the exact mechanism of EBV latency maintenance and thein vivotriggering signal for lytic induction have yet to be elucidated. Previously, we have shown that the EBV microRNA miR-BART20-5p directly targets the immediate early genesBRLF1andBZLF1as well asBcl-2-associated death promoter (BAD) in EBV-associated gastric carcinoma. In this study, we found that both mRNA and protein levels ofBRLF1andBZLF1were suppressed in cells followingBADknockdown and increased afterBADoverexpression. Progeny virus production was also downregulated by specific knockdown ofBAD. Our results demonstrated thatcaspase-3-dependent apoptosis is a prerequisite forBAD-mediated EBV lytic cycle induction. Therefore, our data suggest that miR-BART20-5p plays an important role in latency maintenance and tumor persistence of EBV-associated gastric carcinoma by inhibitingBAD-mediatedcaspase-3-dependent apoptosis, which would trigger immediate early gene expression.IMPORTANCEEBV has an ability to remain latent in host cells, including EBV-associated tumor cells hiding from immune surveillance. However, the exact molecular mechanisms of EBV latency maintenance remain poorly understood. Here, we demonstrated that miR-BART20-5p inhibited the expression of EBV immediate early genes indirectly, by suppressingBAD-inducedcaspase-3-dependent apoptosis, in addition to directly, as we previously reported. Our study suggests that EBV-associated tumor cells might endure apoptotic stress to some extent and remain latent with the aid of miR-BART20-5p. Blocking the expression or function of BART20-5p may expedite EBV-associated tumor cell death via immune attack and apoptosis.

Suppression of JAK-STAT signaling by Epstein-Barr virus tegument protein BGLF2 through recruitment of SHP1 phosphatase and promotion of STAT2 degradation

2021 ◽  
Author(s):  
Sonia Jangra ◽  
Aradhana Bharti ◽  
Wai-Yin Lui ◽  
Vidyanath Chaudhary ◽  
Michael George Botelho ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Suppressive Effect ◽  
Host Cells ◽  
Interferon Response ◽  
Tegument Protein ◽  
Type Ii ◽  
Barr Virus ◽  
Stat Signaling ◽  
Epstein Barr ◽  
Type Iii Ifn

Some lytic proteins encoded by Epstein-Barr virus (EBV) suppress host interferon (IFN) signaling to facilitate viral replication. In this study we sought to identify and characterize EBV proteins antagonizing IFN signaling. The induction of IFN-stimulated genes (ISGs) by IFN-β was effectively suppressed by EBV. A functional screen was therefore performed to identify IFN-antagonizing proteins encoded by EBV. EBV tegument protein BGLF2 was identified as a potent suppressor of JAK-STAT signaling. This activity was found to be independent of its stimulatory effect on p38 and JNK pathways. Association of BGLF2 with STAT2 resulted in more pronounced K48-linked polyubiquitination and proteasomal degradation of the latter. Mechanistically, BGLF2 promoted the recruitment of SHP1 phosphatase to STAT1 to inhibit its tyrosine phosphorylation. In addition, BGLF2 associated with cullin 1 E3 ubiquitin ligase to facilitate its recruitment to STAT2. Consequently, BGLF2 suppressed ISG induction by IFN-β. Furthermore, BGLF2 also suppressed type II and type III IFN signaling, although the suppressive effect on type II IFN response was milder. When pre-treated with IFN-β, host cells became less susceptible to primary infection of EBV. This phenotype was reversed when expression of BGLF2 was enforced. Finally, genetic disruption of BGLF2 in EBV led to more pronounced induction of ISGs. Taken together, our study unveils the roles of BGLF2 not only in the subversion of innate IFN response but also in lytic infection and reactivation of EBV. Importance Epstein-Barr virus (EBV) is an oncogenic virus associated with the development of lymphoid and epithelial malignancies. EBV has to subvert interferon-mediated host antiviral response to replicate and cause diseases. It is therefore of great interest to identify and characterize interferon-antagonizing proteins produced by EBV. In this study we perform a screen to search for EBV proteins that suppress the action of interferons. We further show that BGLF2 protein of EBV is particularly strong in this suppression. This is achieved by inhibiting two key proteins STAT1 and STAT2 that mediate the antiviral activity of interferons. BGLF2 recruits a host enzyme to remove the phosphate group from STAT1 thereby inactivating its activity. BGLF2 also redirects STAT2 for degradation. A recombinant virus in which BGLF2 gene has been disrupted can activate host interferon response more robustly. Our findings reveal a novel mechanism by which EBV BGLF2 protein suppresses interferon signaling.

scholarly journals Mapping the N-Terminal Residues of Epstein-Barr Virus gp42 That Bind gH/gL by Using Fluorescence Polarization and Cell-Based Fusion Assays

2010 ◽  
Vol 84 (19) ◽  
pp. 10375-10385 ◽  
Author(s):  
Fengling Liu ◽  
Gaby Marquardt ◽  
Austin N. Kirschner ◽  
Richard Longnecker ◽  
Theodore S. Jardetzky
Keyword(s):  
Epithelial Cell ◽  
Viral Infection ◽  
B Cell ◽  
Cell Fusion ◽  
Viral Entry ◽  
Fluorescence Polarization ◽  
Epstein Barr Virus ◽  
Host Cells ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) requires at a minimum membrane-associated glycoproteins gB, gH, and gL for entry into host cells. B-cell entry additionally requires gp42, which binds to gH/gL and triggers viral entry into B cells. The presence of soluble gp42 inhibits membrane fusion with epithelial cells by forming a stable heterotrimer of gH/gL/gp42. The interaction of gp42 with gH/gL has been previously mapped to residues 36 to 81 at the N-terminal region of gp42. In this study, we further mapped this region to identify essential features for binding to gH/gL by use of synthetic peptides. Data from fluorescence polarization, cell-cell fusion, and viral infection assays demonstrated that 33 residues corresponding to 44 to 61 and 67 to 81 of gp42 were indispensable for maintaining low-nanomolar-concentration gH/gL binding affinity and inhibiting B-cell fusion and epithelial cell fusion as well as viral infection. Overall, specific, large hydrophobic side chain residues of gp42 appeared to provide critical interactions, determining the binding strength. Mutations of these residues also diminished the inhibition of B-cell and epithelial cell fusions as well as EBV infection. A linker region (residues 62 to 66) between two gH/gL binding regions served as an important spacer, but individual amino acids were not critical for gH/gL binding. Probing the binding site of gH/gL and gp42 with gp42 peptides is critical for a better understanding of the interaction of gH/gL with gp42 as well as for the design of novel entry inhibitors of EBV and related human herpesviruses.

scholarly journals The 3D structure of Kaposi sarcoma herpesvirus LANA C-terminal domain bound to DNA

2015 ◽  
Vol 112 (21) ◽  
pp. 6694-6699 ◽  
Author(s):  
Jan Hellert ◽  
Magdalena Weidner-Glunde ◽  
Joern Krausze ◽  
Heinrich Lünsdorf ◽  
Christiane Ritter ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Epstein Barr Virus ◽  
Kaposi Sarcoma ◽  
Higher Order ◽  
Host Cells ◽  
Nuclear Antigen ◽  
Arbitrary Sequence ◽  
Homologous Proteins ◽  
Barr Virus ◽  
Epstein Barr

Kaposi sarcoma herpesvirus (KSHV) persists as a latent nuclear episome in dividing host cells. This episome is tethered to host chromatin to ensure proper segregation during mitosis. For duplication of the latent genome, the cellular replication machinery is recruited. Both of these functions rely on the constitutively expressed latency-associated nuclear antigen (LANA) of the virus. Here, we report the crystal structure of the KSHV LANA DNA-binding domain (DBD) in complex with its high-affinity viral target DNA, LANA binding site 1 (LBS1), at 2.9 Å resolution. In contrast to homologous proteins such as Epstein-Barr virus nuclear antigen 1 (EBNA-1) of the related γ-herpesvirus Epstein-Barr virus, specific DNA recognition by LANA is highly asymmetric. In addition to solving the crystal structure, we found that apart from the two known LANA binding sites, LBS1 and LBS2, LANA also binds to a novel site, denoted LBS3. All three sites are located in a region of the KSHV terminal repeat subunit previously recognized as a minimal replicator. Moreover, we show that the LANA DBD can coat DNA of arbitrary sequence by virtue of a characteristic lysine patch, which is absent in EBNA-1 of the Epstein-Barr virus. Likely, these higher-order assemblies involve the self-association of LANA into supermolecular spirals. One such spiral assembly was solved as a crystal structure of 3.7 Å resolution in the absence of DNA. On the basis of our data, we propose a model for the controlled nucleation of higher-order LANA oligomers that might contribute to the characteristic subnuclear KSHV microdomains (“LANA speckles”), a hallmark of KSHV latency.

scholarly journals Contribution of Epstein–Barr Virus Latent Proteins to the Pathogenesis of Classical Hodgkin Lymphoma

Pathogens ◽  
2018 ◽  
Vol 7 (3) ◽  
pp. 59 ◽  
Author(s):  
Katerina Vrzalikova ◽  
Taofik Sunmonu ◽  
Gary Reynolds ◽  
Paul Murray
Keyword(s):  
Host Cell ◽  
Hodgkin Lymphoma ◽  
Epstein Barr Virus ◽  
Host Cells ◽  
Classical Hodgkin Lymphoma ◽  
Cellular Functions ◽  
Human Virus ◽  
Barr Virus ◽  
Cell Functions ◽  
Epstein Barr

Pathogenic viruses have evolved to manipulate the host cell utilising a variety of strategies including expression of viral proteins to hijack or mimic the activity of cellular functions. DNA tumour viruses often establish latent infection in which no new virions are produced, characterized by the expression of a restricted repertoire of so-called latent viral genes. These latent genes serve to remodel cellular functions to ensure survival of the virus within host cells, often for the lifetime of the infected individual. However, under certain circumstances, virus infection may contribute to transformation of the host cell; this event is not a usual outcome of infection. Here, we review how the Epstein–Barr virus (EBV), the prototypic oncogenic human virus, modulates host cell functions, with a focus on the role of the EBV latent genes in classical Hodgkin lymphoma.

scholarly journals The Impact of Epstein-Barr Virus Infection on Epigenetic Regulation of Host Cell Gene Expression in Epithelial and Lymphocytic Malignancies

2021 ◽  
Vol 11 ◽  
Author(s):  
Merrin Man Long Leong ◽  
Maria Li Lung
Keyword(s):  
Gene Expression ◽  
Epigenetic Regulation ◽  
Epstein Barr Virus ◽  
Regulation Of Gene Expression ◽  
Host Cells ◽  
Viral Gene ◽  
Epstein Barr Virus Infection ◽  
Barr Virus ◽  
Epstein Barr ◽  
The Impact

Epstein-Barr virus (EBV) infection is associated with a variety of malignancies including Burkitt’s lymphoma (BL), Hodgkin’s disease, T cell lymphoma, nasopharyngeal carcinoma (NPC), and ∼10% of cases of gastric cancer (EBVaGC). Disruption of epigenetic regulation in the expression of tumor suppressor genes or oncogenes has been considered as one of the important mechanisms for carcinogenesis. Global hypermethylation is a distinct feature in NPC and EBVaGC, whereas global reduction of H3K27me3 is more prevalent in EBVaGC and EBV-transformed lymphoblastoid cells. In BL, EBV may even usurp the host factors to epigenetically regulate its own viral gene expression to restrict latency and lytic switch, resulting in evasion of immunosurveillance. Furthermore, in BL and EBVaGC, the interaction between the EBV episome and the host genome is evident with respectively unique epigenetic features. While the interaction is associated with suppression of gene expression in BL, the corresponding activity in EBVaGC is linked to activation of gene expression. As EBV establishes a unique latency program in these cancer types, it is possible that EBV utilizes different latency proteins to hijack the epigenetic modulators in the host cells for pathogenesis. Since epigenetic regulation of gene expression is reversible, understanding the precise mechanisms about how EBV dysregulates the epigenetic mechanisms enables us to identify the potential targets for epigenetic therapies. This review summarizes the currently available epigenetic profiles of several well-studied EBV-associated cancers and the relevant distinct mechanisms leading to aberrant epigenetic signatures due to EBV.

scholarly journals Epstein-Barr virus inactivates the transcriptome and disrupts the chromatin architecture of its host cell in the first phase of lytic reactivation

2019 ◽  
Author(s):  
Alexander Buschle ◽  
Paulina Mrozek-Gorska ◽  
Stefan Krebs ◽  
Helmut Blum ◽  
Filippo M. Cernilogar ◽  
...  
Keyword(s):  
Host Cell ◽  
Epstein Barr Virus ◽  
De Novo ◽  
Human Tumor ◽  
Regulatory Elements ◽  
Lytic Cycle ◽  
Host Cells ◽  
Dependent Manner ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACTEpstein-Barr virus (EBV), a herpes virus also termed HHV 4 and the first identified human tumor virus, establishes a stable long-term latent infection in human B cells, its preferred host. Upon induction of EBV’s lytic phase the latently infected cells turn into a virus factory, a process, that is governed by EBV. In the lytic, productive phase all herpesviruses ensure the efficient induction of all lytic viral genes to produce progeny, but certain of these genes also repress the ensuing antiviral responses of the virally infected host cells, regulate their apoptotic death or control the cellular transcriptome. We now find that EBV causes previously unknown massive and global alterations in the chromatin of its host cell upon induction of the viral lytic phase and prior to the onset of viral DNA replication. The viral initiator protein of the lytic cycle, BZLF1, binds to >105binding sites with different sequence motifs in cellular chromatin and in a concentration dependent manner. Concomitant with DNA binding, silent chromatin opens locally as shown by ATAC-seq experiments, while previously wide-open cellular chromatin becomes inaccessible on a global scale within hours. While viral transcripts increase drastically, the induction of the lytic phase results in a massive reduction of cellular transcripts and a loss of chromatin-chromatin interactions of cellular promoters with their distal regulatory elements as shown in Capture-C experiments. Our data document that EBV’s lytic cycle induces discrete early processes that disrupt the architecture of host cellular chromatin and repress the cellular epigenome and transcriptome likely supporting the efficientde novosynthesis of this herpesvirus.

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