Consideration of Epstein-Barr Virus-Encoded Noncoding RNAs EBER1 and EBER2 as a Functional Backup of Viral Oncoprotein Latent Membrane Protein 1

ABSTRACT The Epstein-Barr virus (EBV)-encoded noncoding RNAs EBER1 and EBER2 are highly abundant through all four latency stages of EBV infection (III-II-I-0) and have been associated with an oncogenic phenotype when expressed in cell lines cultured in vitro . In vivo , EBV-infected B cells derived from freshly isolated lymphocytes show that EBER1/2 deletion does not impair viral latency. Based on published quantitative proteomics data from BJAB cells expressing EBER1 and EBER2, we propose that the EBERs, through their activation of AKT in a B-cell-specific manner, are a functionally redundant backup of latent membrane protein 1 (LMP1)—an essential oncoprotein in EBV-associated malignancies, with a main role in AKT activation. Our proposed model may explain the lack of effect on viral latency establishment in EBER-minus EBV infection.

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Dysregulation of Dual-Specificity Phosphatases by Epstein-Barr Virus LMP1 and Its Impact on Lymphoblastoid Cell Line Survival

Journal of Virology ◽

10.1128/jvi.01837-19 ◽

2019 ◽

Vol 94 (4) ◽

Author(s):

Kai-Min Lin ◽

Sue-Jane Lin ◽

Juin-Han Lin ◽

Pei-Yi Lin ◽

Pu-Lin Teng ◽

...

Keyword(s):

Membrane Protein ◽

Epstein Barr Virus ◽

Latent Membrane Protein ◽

Negative Regulator ◽

Latent Membrane Protein 1 ◽

Barr Virus ◽

Ebv Infection ◽

Dual Specificity ◽

Dual Specificity Phosphatases ◽

Epstein Barr

ABSTRACT The strongest evidence of the oncogenicity of Epstein-Barr virus (EBV) in vitro is its ability to immortalize human primary B lymphocytes into lymphoblastoid cell lines (LCLs). Yet the underlying mechanisms explaining how the virus tempers the growth program of the host cells have not been fully elucidated. The mitogen-activated protein kinases (MAPKs) are implicated in many cellular processes and are constitutively activated in LCLs. We questioned the expression and regulation of the dual-specificity phosphatases (DUSPs), the main negative regulator of MAPKs, during EBV infection and immortalization. Thirteen DUSPs, including 10 typical and 3 atypical types of DUSPs, were tested. Most of them were downregulated after EBV infection. Here, a role of viral oncogene latent membrane protein 1 (LMP1) in limiting DUSP6 and DUSP8 expression was identified. Using MAPK inhibitors, we found that LMP1 activates extracellular signal-regulated kinase (ERK) or p38 to repress the expression of DUSP6 and DUSP8, with corresponding substrate specificity. Morphologically, overexpression of DUSP6 and DUSP8 attenuates the ability of EBV-immortalized LCL cells to clump together. Mechanistically, apoptosis induced by restoring DUSP6 and DUSP8 in LCLs indicated a novel mechanism for LMP1 to provide a survival signal during EBV immortalization. Collectively, this report provides the first description of the interplay between EBV genes and DUSPs and contributes considerably to the interpretation of MAPK regulation in EBV immortalization. IMPORTANCE Infections by the ubiquitous Epstein-Barr virus (EBV) are associated with a wide spectrum of lymphomas and carcinomas. It has been well documented that activation levels of MAPKs are found in cancer cells to translate various external or intrinsic stimuli into cellular responses. Physiologically, the dual-specificity phosphates (DUSPs) exhibit great ability in regulating MAPK activities with respect to their capability of dephosphorylating MAPKs. In this study, we found that DUSPs were generally downregulated after EBV infection. EBV oncogenic latent membrane protein 1 (LMP1) suppressed DUSP6 and DUSP8 expression via MAPK pathway. In this way, LMP1-mediated MAPK activation was a continuous process. Furthermore, DUSP downregulation was found to contribute greatly to prevent apoptosis of EBV-infected cells. To sum up, this report sheds light on a novel molecular mechanism explaining how EBV maintains the unlimited proliferation status of the immortalized cells and provides a new link to understand EBV-induced B cell survival.

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Epstein-Barr Virus Represses the FoxO1 Transcription Factor through Latent Membrane Protein 1 and Latent Membrane Protein 2A

Journal of Virology ◽

10.1128/jvi.00983-06 ◽

2006 ◽

Vol 80 (22) ◽

pp. 11191-11199 ◽

Cited By ~ 20

Author(s):

Angharad M. Shore ◽

Paul C. White ◽

Rosaline C.-Y. Hui ◽

Abdelkader Essafi ◽

Eric W.-F. Lam ◽

...

Keyword(s):

Transcription Factor ◽

Membrane Protein ◽

B Cell ◽

Epstein Barr Virus ◽

Latent Membrane Protein ◽

Latent Membrane Protein 1 ◽

Latent Membrane Protein 2A ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) infection is associated with the development of many B-cell lymphomas, including Burkitt's lymphoma, Hodgkin's lymphoma, and posttransplant lymphoproliferative disease. The virus alters a diverse range of cellular molecules, which leads to B-cell growth and immortalization. This study was initiated to investigate the interplay between EBV and a proapoptotic transcription factor target, FoxO1. In this report, we show that EBV infection of B cells leads to the downregulation of FoxO1 expression by phosphatidylinositol 3-kinase-mediated nuclear export, by inhibition of FoxO1 mRNA expression, and by alteration of posttranslational modifications. This repression directly correlates with the expression of the FoxO1 target gene Bcl-6 and inversely correlates with the FoxO1-regulated gene Cyclin D2. Expression of the EBV genes for latent membrane protein 1 and latent membrane protein 2A decreases FoxO1 expression. Thus, our data elucidate distinct mechanisms for the regulation of the proapoptotic transcription factor FoxO1 by EBV.

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Epstein-Barr Virus Latent Membrane Protein-1 Expression in Nasopharyngeal Carcinoma

JCO Global Oncology ◽

10.1200/go.21.00120 ◽

2021 ◽

pp. 1406-1412

Author(s):

Valerie E. Salano ◽

Amos R. Mwakigonja ◽

Ashfaq Abdulshakoor ◽

Aveline A. Kahinga ◽

Enica M. Richard

Keyword(s):

Nasopharyngeal Carcinoma ◽

Membrane Protein ◽

Epstein Barr Virus ◽

Latent Membrane Protein ◽

Latent Membrane Protein 1 ◽

Female Ratio ◽

Histologic Subtype ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr

PURPOSE Nasopharyngeal carcinoma (NPC), a malignant neoplasm of the epithelium covering the nasopharynx, is a rare disease in most parts of the world. Epstein-Barr virus (EBV), the most potent oncogenic virus, coupled with environmental and genetic factors has been identified to play a role in the development of NPC. An array of methods for detecting the virus do exist, from serologic detection of antibodies to DNA amplification. There is paucity of local data on the status of EBV infection in relation to NPC within the region, and this study attempts to shed more light on the subject. METHODS This was a retrospective cross-sectional laboratory-based study on histologically confirmed, archived tissues from July 2015 to June 2019. Immunohistochemistry expression of latent membrane protein-1 (LMP-1) was used to detect EBV infection in the tissues. RESULTS A total of 71 cases were enrolled in this study. The mean age was 47.87 years ± 16.84 years with a male-to-female ratio of 1.5:1. There was a unimodal distribution of EBV detection, with the peak (26.8%) at 36-45 years. About 45.1% of the 71 samples tested positive for LMP-1, all of which were nonkeratinizing carcinoma. Nonkeratinizing carcinoma was the most common histopathologic subtype (n = 67; 94.4%), with the majority (38 of 67; 56.7%) being undifferentiated and 29 of 67 (43.3%) differentiated. Keratinizing and basaloid subtypes had two cases each, representing 2.8%. CONCLUSION A significant proportion of NPC, particularly nonkeratinizing histologic subtype, seems to show LMP-1 positivity by immunohistochemistry, which may be adopted in resource-constrained settings to detect EBV infection in these tissue biopsies.

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Epstein-Barr virus encoded latent membrane protein 1 (LMP1) and TNF receptor associated factors (TRAF): colocalisation of LMP1 and TRAF1 in primary EBV infection and in EBV associated Hodgkin lymphoma

Molecular Pathology ◽

10.1136/mp.56.3.156 ◽

2003 ◽

Vol 56 (>3) ◽

pp. 156-161 ◽

Cited By ~ 15

Author(s):

G Siegler

Keyword(s):

Membrane Protein ◽

Hodgkin Lymphoma ◽

Associated Factors ◽

Epstein Barr Virus ◽

Latent Membrane Protein ◽

Latent Membrane Protein 1 ◽

Tnf Receptor ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr

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Sequence Variations of Epstein-Barr Virus-Encoded Small Noncoding RNA and Latent Membrane Protein 1 in Hematologic Tumors in Northern China

Intervirology ◽

10.1159/000510398 ◽

2021 ◽

Vol 64 (2) ◽

pp. 69-80

Author(s):

Hai-Yu Wang ◽

Lingling Sun ◽

Ping Li ◽

Wen Liu ◽

Zhong-Guang Zhang ◽

...

Keyword(s):

Membrane Protein ◽

Nested Pcr ◽

Noncoding Rna ◽

Epstein Barr Virus ◽

Northern China ◽

Latent Membrane Protein ◽

Latent Membrane Protein 1 ◽

Small Noncoding Rna ◽

Barr Virus ◽

Epstein Barr

Objective: To investigate the relationship between hematologic tumors and Epstein-Barr virus (EBV)-encoded small noncoding RNA (EBER) variations as well as latent membrane protein 1 (LMP1) variations. Methods: Patients with leukemia and myelodysplastic syndrome (MDS) were selected as subjects. Genotypes 1/2 and genotypes F/f were analyzed using the nested PCR technology, while EBER and LMP1 subtypes were analyzed by the nested PCR and DNA sequencing. Results: Type 1 was more dominant than type 2, found in 59 out of 82 (72%) leukemia and in 31 out of 35 (88.6%) MDS, while type F was more prevalent than type f in leukemia (83/85, 97.6%) and MDS (29/31, 93.5%) samples. The distribution of EBV genotypes 1/2 was not significantly different among leukemia, MDS, and healthy donor groups, neither was that of EBV genotypes F/f. EB-6m prototype was the dominant subtype of EBER in leukemia and MDS (73.2% [30/41] and 83.3% [10/12], respectively). The frequency of EB-6m was lower than that of healthy people (96.7%, 89/92), and the difference was significant (p < 0.05). China 1 subtype was the dominant subtype of LMP1 in leukemia and MDS (70% [28/40] and 90% [9/10], respectively), and there was no significant difference in the distribution of LMP1 subtypes among the 3 groups (p > 0.05). Conclusion: The distribution of EBV 1/2, F/f, EBER, and LMP1 subtypes in leukemia and MDS was similar to that in the background population in Northern China, which means that these subtypes may be rather region-restricted but not associated with leukemia and MDS pathogenesis.

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