Pathways of activation of the Epstein-Barr virus productive cycle

Sinclair, Alison J.; Brimmell, Matthew; Shanahan, Fergus; Farrell, Paul J.

doi:10.1128/jvi.65.5.2237-2244.1991

Cited by 112 publications

(62 citation statements)

References 36 publications

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“…These observations suggested that both proteins have redundant properties. An additional level of complexity stems from the observation that the BZLF1 protein activates the promoters of BZLF1 and BRLF1 and, vice versa, the BRLF1 gene product up‐regulates the expression of the BZLF1 gene (Sinclair et al ., 1991; Ragoczy et al ., 1998).…”

Section: Introductionmentioning

confidence: 99%

The Epstein-Barr virus lytic program is controlled by the co-operative functions of two transactivators

Feederle¹,

Kost²,

Baumann³

et al. 2000

The EMBO Journal

353

408

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The propagation of herpesviruses has long been viewed as a temporally regulated sequential process that results from the consecutive expression of speci®c viral transactivators. As a key step in this process, lytic viral DNA replication is considered as a checkpoint that controls the expression of the late structural viral genes. In a novel genetic approach, we show that both hypotheses do not hold true for the Epstein±Barr virus (EBV). The study of viral mutants of EBV in which the early genes BZLF1 and BRLF1 are deleted allowed a precise assignment of the function of these proteins. Both transactivators were absolutely essential for viral DNA replication. Both BZLF1 and BRLF1 were required for full expression of the EBV proteins expressed during the lytic program, although the respective in¯uence of these molecules on the expression of various viral target genes varied greatly. In replication-defective viral mutants, neither early gene expression nor DNA replication was a prerequisite for late gene expression. This work shows that BRLF1 and BZLF1 harbor distinct but complementary functions that in¯uence all stages of viral production.

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Section: Introductionmentioning

confidence: 99%

The Epstein-Barr virus lytic program is controlled by the co-operative functions of two transactivators

Feederle¹,

Kost²,

Baumann³

et al. 2000

The EMBO Journal

353

408

View full text Add to dashboard Cite

show abstract

“…BRLF1 is translated from a bicistronic mRNA which also encodes another IE gene product, BZLF1 (12,20). These two EBV gene products function in activating expression from a number of viral (3,5,8,13,15,18,28) and perhaps cellular (7) promoters, thereby initiating the lytic cascade. However, HVS R RNA is expressed as an early transcript in HVS-infected cells (23,25).…”

mentioning

confidence: 99%

The herpesvirus saimiri ORF50 gene, encoding a transcriptional activator homologous to the Epstein-Barr virus R protein, is transcribed from two distinct promoters of different temporal phases

Whitehouse

Carr

Griffiths

et al. 1997

J Virol

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The mRNA species encoding the herpesvirus saimiri (HVS) homolog of the Epstein-Barr virus R transcriptional activator (termed ORF50) have been identified and used to determine transcriptional start sites within the gene. The first transcript is spliced and starts from a promoter within ORF49 containing a single intron; the second is produced from a promoter within the second exon and is in the same reading frame. The spliced transcript is detected at early times during productive virus replication in OMK cells, whereas the nonspliced transcript is detected later. The spliced transcript is fivefold-more potent in activating the delayed-early ORF6 promoter; the function of the nonspliced transcript is unclear. Thus, the role of this protein in activating herpesvirus saimiri from the latent state may differ significantly from that of the Epstein-Barr virus R protein.Herpesvirus saimiri (HVS) establishes asymptomatic infections involving a subset of T lymphocytes in its natural host, the squirrel monkey (Saimiri sciureus), but causes fatal T-cell lymphomas and lymphoproliferative diseases in other species of New World primates (6). HVS has been classified as a gamma-2 herpesvirus and shares significant homology with Epstein-Barr virus (EBV) (1,2,9,10,16,24). The genomes of HVS and EBV are generally colinear, in that homologous genes are found in approximately equivalent locations and in the same relative orientations in the two viruses (22). As in many other herpesviruses, gene expression during lytic infection occurs in three main temporal phases: immediate-early (IE), delayed-early (DE), and late (17). The major IE transcript in HVS is encoded by the HindIII-G IE gene (ORF14) (2,(25)(26)(27). Analysis of the sequence shows that it does not exhibit homology with any EBV-encoded proteins (25), but it does contain local homology with a putative superantigen (29); however, its function remains to be established. The 52-kDa product of the HVS IE gene (ORF57) is homologous to the EBV transactivator encoded by BMLF1 (also known as Mta, M-IE, or IE-2) and to the 27-kDa or IE 63-kDa protein encoded by UL54 of herpes simplex virus 1 and RF4 of varicellazoster virus (4,14,21,22,24).The EcoRI-D or HVS R protein transactivator (ORF50) is homologous to the BRLF1 gene product (also known as R or Rta) (23). BRLF1 is translated from a bicistronic mRNA which also encodes another IE gene product, BZLF1 (12, 20). These two EBV gene products function in activating expression from a number of viral (3,5,8,13,15,18,28) and perhaps cellular (7) promoters, thereby initiating the lytic cascade. However, HVS R RNA is expressed as an early transcript in HVS-infected cells (23, 25). The HVS R gene is proposed to be spliced with more than one exon, although the initiation codon has not been mapped. Despite the likelihood of a spliced transcript, there is evidence that a DNA sequence within the identified exon is able to produce a functionally active protein capable of activating a DE ORF6 gene promoter, a component of the major DNA binding prot...

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“…Besides transcriptional control, Zta is regulated by posttranslational modifications such as phosphorylation (8), cellular localization (3), and protein-protein interactions (13,17,18,42,51). Zta can be translated from two different transcripts starting in either the BZLF1 or BRLF1 promoter (22,41), the latter giving rise to the expression of a bicistronic message coding for both Zta and Rta. Both transcripts are localized in a region covered also by the intron of the EBNA1 primary transcript.…”

mentioning

confidence: 99%

Epstein-Barr virus lytic replication is controlled by posttranscriptional negative regulation of BZLF1

Prang

Wolf

Schwarzmann

1995

J Virol

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Regulation of the immediate-early gene BZLF1 is assumed to play a key role in triggering the lytic replication of Epstein-Barr virus (EBV). The expression of BZLF1 is regulated on multiple levels, including control of transcription by several positive and negative cis-acting elements as well as posttranslational modifications and protein-protein interactions. Localization of BZLF1 on one strand of the genome and the latent EBNA1 transcription unit on the complementary strand suggests a regulatory mechanism via hybridization of antisense RNA. With a plasmid encoding a defective BZLF1 RNA, which could not be translated, we were able to induce expression of endogenous BZLF1 gene product Zta and other proteins of the lytic cycle. Our data show for the first time that latent replication is stabilized by negative regulation of an immediate-early gene of the lytic cycle by a posttranscriptional mechanism. This might be a common theme of herpes simplex virus and EBV latency.

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Pathways of activation of the Epstein-Barr virus productive cycle

Cited by 112 publications

References 36 publications

The Epstein-Barr virus lytic program is controlled by the co-operative functions of two transactivators

The Epstein-Barr virus lytic program is controlled by the co-operative functions of two transactivators

The herpesvirus saimiri ORF50 gene, encoding a transcriptional activator homologous to the Epstein-Barr virus R protein, is transcribed from two distinct promoters of different temporal phases

Epstein-Barr virus lytic replication is controlled by posttranscriptional negative regulation of BZLF1

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