The Late Lytic LMP-1 Protein of Epstein-Barr Virus Can Negatively Regulate LMP-1 Signaling

ABSTRACT The BNLF-1 open reading frame of Epstein-Barr virus (EBV) encodes two related proteins, latent membrane protein-1 (LMP-1) and lytic LMP-1 (lyLMP-1). LMP-1 is a latent protein required for immortalization of human B cells by EBV, whereas lyLMP-1 is expressed during the lytic cycle and is found in the EBV virion. We show here that, in contrast to LMP-1, lyLMP-1 is stable, with a half-life of >20 h in tetradecanoyl phorbol acetate- and butyrate-treated B95-8 cells. Although lyLMP-1 itself has negligible effects on NF-κB activity, it inhibits NF-κB activation by LMP-1 in a dose-dependent manner. The lyLMP-1 protein does not oligomerize with LMP-1, and the negative effect of lyLMP-1 on NF-κB activation by LMP-1 does not result from lyLMP-1-mediated disruption of LMP-1 oligomers. Modulation of LMP-1-activated signaling pathways is the first identified biological activity associated with lyLMP-1, and this activity may contribute to the progression of EBV's lytic cycle.

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Unexpected Absence of the Epstein-Barr Virus (EBV) lyLMP-1 Open Reading Frame in Tumor Virus Isolates: Lack of Correlation between Met129 Status and EBV Strain Identity

Journal of Virology ◽

10.1128/jvi.77.7.4415-4422.2003 ◽

2003 ◽

Vol 77 (7) ◽

pp. 4415-4422 ◽

Cited By ~ 9

Author(s):

Kimberly D. Erickson ◽

Christoph Berger ◽

William F. Coffin ◽

Edwin Schiff ◽

Dennis M. Walling ◽

...

Keyword(s):

Cell Lines ◽

Epstein Barr Virus ◽

Open Reading Frame ◽

Lytic Cycle ◽

Reading Frame ◽

Barr Virus ◽

Tumor Virus ◽

Epstein Barr ◽

Virus Isolates ◽

Codon 129

ABSTRACT The lytic cycle-associated lytic latent membrane protein-1 (lyLMP-1) of Epstein-Barr virus (EBV) is an amino-terminally truncated form of the oncogenic LMP-1. Although lyLMP-1 shares none of LMP-1's transforming and signal transducing activities, we recently reported that lyLMP-1 can negatively regulate LMP-1-stimulated NF-κB activation. The lyLMP-1 protein encoded by the B95-8 strain of EBV initiates from methionine 129 (Met129) of the LMP-1 open reading frame (ORF). The recent report that Met129 in the B95-8 LMP-1 ORF is not conserved in the Akata strain of EBV prompted us to screen a panel of EBV-positive cell lines for conservation of Met129 and lyLMP-1 expression. We found that 15 out of 16 tumor-associated virus isolates sequenced encoded an ATT or ACC codon in place of ATG in the LMP-1 ORF at position 129, and tumor cell lines harboring isolates lacking an ATG at codon 129 did not express the lyLMP-1 protein. In contrast, we found that EBV DNA from 22 out of 37 healthy seropositive donors retained the Met129 codon. Finally, the lyLMP-1 initiator occurs variably within distinct EBV strains and its presence cannot be predicted by EBV strain identity. Thus, Met129 is not peculiar to the B95-8 strain of EBV, but rather can be found in the background of several evolutionarily distinct EBV strains. Its absence from EBV isolates from tumors raises the possibility of selective pressure on Met129 in EBV-dependent tumors.

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Epstein–Barr Virus BALF0 and BALF1 Modulate Autophagy

Viruses ◽

10.3390/v11121099 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1099

Author(s):

Zhouwulin Shao ◽

Chloé Borde ◽

Frédérique Quignon ◽

Alexandre Escargueil ◽

Vincent Maréchal

Keyword(s):

Cell Survival ◽

Epstein Barr Virus ◽

Viral Proteins ◽

Open Reading Frame ◽

Lytic Cycle ◽

Reading Frame ◽

Barr Virus ◽

Viral Particles ◽

Epstein Barr ◽

Catabolic Process

Autophagy is an essential catabolic process that degrades cytoplasmic components within the lysosome, therefore ensuring cell survival and homeostasis. A growing number of viruses, including members of the Herpesviridae family, have been shown to manipulate autophagy to facilitate their persistence or optimize their replication. Previous works showed that the Epstein–Barr virus (EBV), a human transforming gammaherpesvirus, hijacked autophagy during the lytic phase of its cycle, possibly to favor the formation of viral particles. However, the viral proteins that are responsible for an EBV-mediated subversion of the autophagy pathways remain to be characterized. Here we provide the first evidence that the BALF0/1 open reading frame encodes for two conserved proteins of the Bcl-2 family, BALF0 and BALF1, that are expressed during the early phase of the lytic cycle and can modulate autophagy. A putative LC3-interacting region (LIR) has been identified that is required both for BALF1 colocalization with autophagosomes and for its ability to stimulate autophagy.

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

10.1101/573659 ◽

2019 ◽

Cited By ~ 2

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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The lytic cycle of Epstein-Barr virus in the nonproducer Raji line can be rescued by the expression of a 135-kilodalton protein encoded by the BALF2 open reading frame.

Journal of Virology ◽

10.1128/jvi.69.11.7309-7314.1995 ◽

1995 ◽

Vol 69 (11) ◽

pp. 7309-7314 ◽

Cited By ~ 38

Author(s):

G Decaussin ◽

V Leclerc ◽

T Ooka

Keyword(s):

Epstein Barr Virus ◽

Open Reading Frame ◽

Lytic Cycle ◽

Reading Frame ◽

Barr Virus ◽

Epstein Barr

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Latent Membrane Protein 1 Inhibits Epstein-Barr Virus Lytic Cycle Induction and Progress via Different Mechanisms

Journal of Virology ◽

10.1128/jvi.77.8.5000-5007.2003 ◽

2003 ◽

Vol 77 (8) ◽

pp. 5000-5007 ◽

Cited By ~ 44

Author(s):

Stuart Prince ◽

Sinead Keating ◽

Ceri Fielding ◽

Paul Brennan ◽

Eike Floettmann ◽

...

Keyword(s):

B Cells ◽

Membrane Protein ◽

Epstein Barr Virus ◽

Latent Membrane Protein ◽

Lytic Cycle ◽

Latent Membrane Protein 1 ◽

Barr Virus ◽

Human B Cells ◽

Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) is a potent growth-transforming agent of human B cells. It has previously been shown that viral latent membrane protein 1 (LMP1) is essential for EBV-induced transformation of normal B cells and contributes to maintenance of latency in vitro. Using the EBV-positive Burkitt's lymphoma line P3HR1-c16, which lacks LMP1 during latency and which can readily be activated into virus-productive lytic cycle, we found that LMP1 inhibits lytic cycle induction via the transcription factor NF-κB. In addition, LMP1 inhibits lytic cycle progress via two distinct NF-κB-independent mechanisms: one involving the cytosolic C-terminal activating regions and the other involving the transmembrane region of LMP1. These findings indicate that in B cells EBV self-limits its lytic cycle via three distinct LMP1-mediated mechanisms.

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Vitamin E inhibits cyclosporin A and H2O2 promoted epstein–barr virus (EBV) transformation of human B cells as assayed by EBV oncogene LMP1 expression

Journal of Surgical Research ◽

10.1016/s0022-4804(03)00187-2 ◽

2003 ◽

Vol 113 (2) ◽

pp. 228-233 ◽

Cited By ~ 5

Author(s):

Changguo Chen ◽

K.S Reddy ◽

T.D Johnston ◽

T.T Khan ◽

D Ranjan

Keyword(s):

Vitamin E ◽

B Cells ◽

Cyclosporin A ◽

Epstein Barr Virus ◽

Barr Virus ◽

Human B Cells ◽

Lmp1 Expression ◽

Ebv Transformation ◽

Epstein Barr

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Chromosomal rearrangements after ex vivo Epstein–Barr virus (EBV) infection of human B cells

Oncogene ◽

10.1038/onc.2009.359 ◽

2009 ◽

Vol 29 (4) ◽

pp. 503-515 ◽

Cited By ~ 45

Author(s):

S Lacoste ◽

E Wiechec ◽

A G dos Santos Silva ◽

A Guffei ◽

G Williams ◽

...

Keyword(s):

B Cells ◽

Epstein Barr Virus ◽

Ex Vivo ◽

Chromosomal Rearrangements ◽

Barr Virus ◽

Ebv Infection ◽

Human B Cells ◽

Epstein Barr

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DNA-binding-defective mutants of the Epstein-Barr virus lytic switch activator Zta transactivate with altered specificities

Molecular and Cellular Biology ◽

10.1128/mcb.14.5.3041-3052.1994 ◽

1994 ◽

Vol 14 (5) ◽

pp. 3041-3052

Author(s):

E K Flemington ◽

J P Lytle ◽

C Cayrol ◽

A M Borras ◽

S H Speck

Keyword(s):

Dna Binding ◽

Epstein Barr Virus ◽

Lytic Cycle ◽

Promoter Elements ◽

Barr Virus ◽

Binding Forms ◽

Viral Genes ◽

Direct Binding ◽

Epstein Barr ◽

Necessary And Sufficient

The Epstein-Barr virus BRLF1 and BZLF1 genes are the first viral genes transcribed upon induction of the viral lytic cycle. The protein products of both genes (referred to here as Rta and Zta, respectively) activate expression of other viral genes, thereby initiating the lytic cascade. Among the viral antigens expressed upon induction of the lytic cycle, however, Zta is unique in its ability to disrupt viral latency; expression of the BZLF1 gene is both necessary and sufficient for triggering the viral lytic cascade. We have previously shown that Zta can activate its own promoter (Zp), through binding to two Zta recognition sequences (ZIIIA and ZIIIB). Here we describe mutant Zta proteins that do not bind DNA (referred to as Zta DNA-binding mutants [Zdbm]) but retain the ability to transactivate Zp. Consistent with the inability of these mutants to bind DNA, transactivation of Zp by Zdbm is not dependent on the Zta recognition sequences. Instead, transactivation by Zdbm is dependent upon promoter elements that bind cellular factors. An examination of other viral and cellular promoters identified promoters that are weakly responsive or unresponsive to Zdbm. An analysis of a panel of artificial promoters containing one copy of various promoter elements demonstrated a specificity for Zdbm activation that is distinct from that of Zta. These results suggest that non-DNA-binding forms of some transactivators retain the ability to transactivate specific target promoters without direct binding to DNA.

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