The Latent Membrane Protein 1 (LMP1)

Kieser, Arnd; Sterz, Kai R.

doi:10.1007/978-3-319-22834-1_4

Cited by 123 publications

(145 citation statements)

References 205 publications

(234 reference statements)

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“…Since LMP1 is also a potent activator of both canonical and noncanonical NF-B, as well as PI3K (56), it may at least partially substitute for the survival effects of LMP2A. In addition, EBV-infected B cells can be activated by CD40L expressed on CD4 T cells in this model, which would likewise result in NF-B and PI3K signaling.…”

Section: Discussionmentioning

confidence: 89%

Latent Membrane Protein 1 (LMP1) and LMP2A Collaborate To Promote Epstein-Barr Virus-Induced B Cell Lymphomas in a Cord Blood-Humanized Mouse Model but Are Not Essential

Dong

Tsai

Romero-Masters

et al. 2017

J Virol

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Epstein-Barr virus (EBV) infection is associated with B cell lymphomas in humans. The ability of EBV to convert human B cells into long-lived lymphoblastoid cell lines (LCLs) in vitro requires the collaborative effects of EBNA2 (which hijacks Notch signaling), latent membrane protein 1 (LMP1) (which mimics CD40 signaling), and EBV-encoded nuclear antigen 3A (EBNA3A) and EBNA3C (which inhibit oncogene-induced senescence and apoptosis). However, we recently showed that an LMP1-deleted EBV mutant induces B cell lymphomas in a newly developed cord blood-humanized mouse model that allows EBV-infected B cells to interact with CD4 T cells (the major source of CD40 ligand). Here we examined whether the EBV LMP2A protein, which mimics constitutively active B cell receptor signaling, is required for EBV-induced lymphomas in this model. We find that the deletion of LMP2A delays the onset of EBV-induced lymphomas but does not affect the tumor phenotype or the number of tumors. The simultaneous deletion of both LMP1 and LMP2A results in fewer tumors and a further delay in tumor onset. Nevertheless, the LMP1/LMP2A double mutant induces lymphomas in approximately half of the infected animals. These results indicate that neither LMP1 nor LMP2A is absolutely essential for the ability of EBV to induce B cell lymphomas in the cord blood-humanized mouse model, although the simultaneous loss of both LMP1 and LMP2A decreases the proportion of animals developing tumors and increases the time to tumor onset. Thus, the expression of either LMP1 or LMP2A may be sufficient to promote early-onset EBV-induced tumors in this model. IMPORTANCE EBV causes human lymphomas, but few models are available for dissecting how EBV causes lymphomas in vivo in the context of a host immune response. We recently used a newly developed cord blood-humanized mouse model to show that EBV can cooperate with human CD4 T cells to cause B cell lymphomas even when a major viral transforming protein, LMP1, is deleted. Here we examined whether the EBV protein LMP2A, which mimics B cell receptor signaling, is required for EBV-induced lymphomas in this model. We find that the deletion of LMP2A alone has little effect on the ability of EBV to cause lymphomas but delays tumor onset. The deletion of both LMP1 and LMP2A results in a smaller number of lymphomas in infected animals, with an even more delayed time to tumor onset. These results suggest that LMP1 and LMP2A collaborate to promote early-onset lymphomas in this model, but neither protein is absolutely essential.KEYWORDS EBV, Epstein-Barr virus, LMP1, LMP2A, humanized mouse, lymphoma

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Section: Discussionmentioning

confidence: 89%

Latent Membrane Protein 1 (LMP1) and LMP2A Collaborate To Promote Epstein-Barr Virus-Induced B Cell Lymphomas in a Cord Blood-Humanized Mouse Model but Are Not Essential

Dong

Tsai

Romero-Masters

et al. 2017

J Virol

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“…Intriguingly, the large majority of cases of cHL carrying inactivating immunoglobulin gene mutations are EBV‐positive, suggesting that EBV infection of a HRS progenitor cell within GC microenvironment may promote survival and further malignant evolution of these pre‐apoptotic precursors. Indeed, EBV is able to immortalize BCR‐negative B cells in vitro and has the capacity to rescue from apoptosis B lymphocytes missing functional BCR, mainly thanks to the ability of LMP‐1 and LMP‐2 to mimic CD40‐ and BCR‐mediated signaling . Nevertheless, the restricted latency II pattern is unable to convey a strong growth‐promoting stimulus in B lymphocytes, an effect that is probably due to the inadequate differentiation state of the precursor cells, which lack the B‐cell specific transcription factors that are required for the expression of EBNA‐2, the main driver of B‐cell proliferation.…”

Section: Microenvironmental Impact Of Ebv Infectionmentioning

confidence: 99%

The impact of EBV and HIV infection on the microenvironmental niche underlying Hodgkin lymphoma pathogenesis

et al. 2016

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The pathogenesis of classical Hodgkin lymphoma (cHL) is still enigmatic, largely because its tumor cells, the so-called Hodgkin and Reed-Stenberg (HRS) cells, invariably reside in a prominent reactive microenvironment, are rare and therefore difficult to analyze. On the other hand, the broadly investigated cHL-derived cell lines are not unequivocally considered as suitable and representative models for this puzzling disease. Based on current knowledge, it appears that the cross talk between the tumor cells and the reactive infiltrate of the microenvironment is complex and that multiple mechanisms occur, making cHL a very heterogeneous disease. In 20-40% of cHL cases, HRS cells carry a monoclonal infection by Epstein Barr virus (EBV), which is considered a tumor-initiating factor. In these cases, EBV shows a latency type II infection pattern with the expression of latent membrane protein-1 (LMP-1), a viral oncoprotein that mimics CD40 activation. This scenario is particularly intriguing for the pathogenesis of cHL arising in HIV-infected patients, which, for still obscure reasons, is invariably EBV-associated with LMP-1 expression in HRS cells. Recent evidences are consistent with the occurrence of different pathogenic pathways variably triggered by virus infections (EBV and HIV), genetic alterations, and interactions with critical microenvironmental components. This review focuses on the different microenvironmental niches that characterize cHL of the general population as well as cases of HIV-infected patients. A more comprehensive understanding of the complex interplay existing between HRS and tumor microenvironment is pivotal for the development of more effective treatments, particularly for relapsed or refractory diseases.

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“…Since LMP1 promotes the expression of host genes associated with tumorigenesis and cell growth (42) epigenetic effects of PARP1, we assessed whether LMP1-mediated changes in gene expression through PARP1 contribute to cellular transformation. The induction of focus formation in the Rat1 cell line is a well-established assay to measure LMP1-mediated transformation (43).…”

Section: Ectopic Expression Of Lmp1 In Mef Parp1mentioning

confidence: 99%

Epstein-Barr Virus Oncoprotein LMP1 Mediates Epigenetic Changes in Host Gene Expression through PARP1

Martin

Lupey

Tempera

2016

J Virol

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The latent infection of Epstein-Barr virus (EBV) is associated with 1% of human cancer incidence. Poly(ADP-ribosyl)ation (PARylation) is a posttranslational modification catalyzed by poly(ADP-ribose) polymerases (PARPs) that mediate EBV replication during latency. In this study, we detail the mechanisms that drive cellular PARylation during latent EBV infection and the effects of PARylation on host gene expression and cellular function. EBV-infected B cells had higher PAR levels than EBV-negative B cells. Moreover, cellular PAR levels were up to 2-fold greater in type III than type I latently infected EBV B cells. We identified a positive association between expression of the EBV genome-encoded latency membrane protein 1 (LMP1) and PAR levels that was dependent upon PARP1. PARP1 regulates gene expression by numerous mechanisms, including modifying chromatin structure and altering the function of chromatin-modifying enzymes. Since LMP1 is essential in establishing EBV latency and promoting tumorigenesis, we explored the model that disruption in cellular PARylation, driven by LMP1 expression, subsequently promotes epigenetic alterations to elicit changes in host gene expression. PARP1 inhibition resulted in the accumulation of the repressive histone mark H3K27me3 at a subset of LMP1-regulated genes. Inhibition of PARP1, or abrogation of PARP1 expression, also suppressed the expression of LMP1-activated genes and LMP1-mediated cellular transformation, demonstrating an essential role for PARP1 activity in LMP1-induced gene expression and cellular transformation associated with LMP1. In summary, we identified a novel mechanism by which LMP1 drives expression of host tumor-promoting genes by blocking generation of the inhibitory histone modification H3K27me3 through PARP1 activation. IMPORTANCEEBV is causally linked to several malignancies and is responsible for 1% of cancer incidence worldwide. The EBV-encoded protein LMP1 is essential for promoting viral tumorigenesis by aberrant activation of several well-known intracellular signaling pathways. We have identified and defined an additional novel molecular mechanism by which LMP1 regulates the expression of tumor-promoting host genes. We found that LMP1 activates the cellular protein PARP1, leading to a decrease in a repressive histone modification, accompanied by induction in expression of multiple cancer-related genes. PARP1 inhibition or depletion led to a decrease in LMP1-induced cellular transformation. Therefore, targeting PARP1 activity may be an effective treatment for EBV-associated malignancies. The Epstein-Barr virus (EBV) is a human gammaherpesvirus that latently infects approximately 95% of the population worldwide (1). Latent EBV infection contributes to 1% of human cancers, including Burkitt's lymphoma and nasopharyngeal carcinoma (2, 3). To establish a latent infection in a naive B cell, EBV first adopts a type III latent gene expression program in which all latency genes are expressed to provide intracellular signals to the infected B cell th...

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The Latent Membrane Protein 1 (LMP1)

Cited by 123 publications

References 205 publications

Latent Membrane Protein 1 (LMP1) and LMP2A Collaborate To Promote Epstein-Barr Virus-Induced B Cell Lymphomas in a Cord Blood-Humanized Mouse Model but Are Not Essential

Latent Membrane Protein 1 (LMP1) and LMP2A Collaborate To Promote Epstein-Barr Virus-Induced B Cell Lymphomas in a Cord Blood-Humanized Mouse Model but Are Not Essential

The impact of EBV and HIV infection on the microenvironmental niche underlying Hodgkin lymphoma pathogenesis

Epstein-Barr Virus Oncoprotein LMP1 Mediates Epigenetic Changes in Host Gene Expression through PARP1

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