Epstein-Barr Virus (EBV) SM Protein Induces and Recruits Cellular Sp110b To Stabilize mRNAs and Enhance EBV Lytic Gene Expression

Nicewonger, John; Suck, Garnet; Bloch, Donald B.; Swaminathan, Sankar

doi:10.1128/jvi.78.17.9412-9422.2004

Cited by 60 publications

(51 citation statements)

References 46 publications

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“…2B). Since CMV promoter activity is not affected by SM (47,61), these results indicate that SM could actually enhance accumulation of BHRF1 mRNA posttranscriptionally, similar to its effect on the majority of EBV transcripts (25). Nevertheless, since the net effect of SM on BHRF1 expression during EBV replication was inhibitory, it appeared likely that SM inhibits the activity of the BHRF1 promoter in the EBV genome during lytic replication.…”

Section: Resultsmentioning

confidence: 76%

“…The BHRF1 gene contains an intron 5Ј to the single open reading frame, suggesting the possibility that SM inhibited BHRF1 expression posttranscriptionally (51). In addition, SM has not been shown to inhibit transcription when its effects on transcription have been directly examined by nuclear run-on assays (47,61). We therefore asked whether SM would inhibit BHRF1 expression when the intron-containing gene was transcribed from a heterologous promoter.…”

Section: Resultsmentioning

confidence: 99%

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Negative Autoregulation of Epstein-Barr Virus (EBV) Replicative Gene Expression by EBV SM Protein

Verma

Chen

Johannsen

et al. 2009

J Virol

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The Epstein-Barr virus (EBV) SM protein is essential for lytic EBV DNA replication and virion production. When EBV replication is induced in cells infected with an SM-deleted recombinant EBV, approximately 50% of EBV genes are expressed inefficiently. When EBV replication is rescued by transfection of SM, SM enhances expression of these genes by direct and indirect mechanisms. While expression of most EBV genes is either unaffected or enhanced by SM, expression of several genes is decreased in the presence of SM. Expression of BHRF1, a homolog of cellular bcl-2, is particularly decreased in the presence of SM. Investigation of the mechanism of BHRF1 downregulation revealed that SM downregulates expression of the immediate-early EBV transactivator R. In EBV-infected cells, R-responsive promoters, including the BHRF1 and SM promoters, were less active in the presence of SM, consistent with SM inhibition of R expression. SM decreased spliced R mRNA levels, supporting a posttranscriptional mechanism of R inhibition. R and BHRF1 expression were also found to decrease during later stages of EBV lytic replication in EBV-infected lymphoma cells. These data indicate that feedback regulation of immediate-early and early genes occurs during the lytic cycle of EBV regulation. Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that infects epithelial and lymphoid cells and is associated with several human malignancies (for a review, see reference 59).EBV undergoes lytic replication in epithelial cells during primary infection and during reactivation from latent infection in B lymphocytes. The switch from latency to lytic replication is regulated by two EBV transcriptional activators: Z (also known as BZLF1, Zta, or ZEBRA) and R (also known as BRLF1 or Rta) (for a review, see reference 68). SM (also known as Mta, EB2, or BMLF1) is an RNA-binding EBV protein that is expressed following Z and R and enhances EBV gene expression by multiple posttranscriptional mechanisms (4,11,28,29,35,61,65). SM is essential for the lytic phase of EBV replication and virion production (21). We previously used an epithelial cell line carrying an EBV recombinant deleted for SM (293 BMLF1-KO) to compare gene expression in the presence and absence of SM (25). When cells carrying recombinant SM-deleted EBV were transfected with the EBV transactivator BZLF1 gene, approximately 50% of EBV genes were expressed poorly but were rescued by cotransfection with SM, resulting in EBV DNA replication and virion production (25). The block in EBV DNA replication is at least partly due to inefficient expression of EBV DNA polymerase and primase in the absence of the SM protein. Transfection of EBV DNA polymerase and primase genes with BZLF1 allows EBV DNA replication but does not rescue virion production, indicating that additional essential EBV mRNAs directly require SM for efficient expression (25).When EBV lytic replication was rescued by SM transfection, expression of most EBV genes either was upregulated or was not significantly changed, but BHRF1 mRN...

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Section: Resultsmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Negative Autoregulation of Epstein-Barr Virus (EBV) Replicative Gene Expression by EBV SM Protein

Verma

Chen

Johannsen

et al. 2009

J Virol

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“…SM is thought to bind to EBV mRNAs in the nucleus and to enhance mRNA export by recruiting cellular export factors (3,7,18). In addition, SM enhances the nuclear accumulation of target mRNAs, suggesting that SM also increases RNA stability (28,35). SM binds to mRNA targets in vivo, which can be coimmunoprecipitated with SM (33).…”

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confidence: 99%

General and Target-Specific RNA Binding Properties of Epstein-Barr Virus SM Posttranscriptional Regulatory Protein

Han

Verma

Hilscher³

et al. 2009

J Virol

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Epstein-Barr virus (EBV) SM protein is an essential nuclear shuttling protein expressed by EBV early during the lytic phase of replication. SM acts to increase EBV lytic gene expression by binding EBV mRNAs and enhancing accumulation of the majority of EBV lytic cycle mRNAs. SM increases target mRNA stability and nuclear export, in addition to modulating RNA splicing. SM and its homologs in other herpesvirus have been hypothesized to function in part by binding viral RNAs and recruiting cellular export factors. Although activation of gene expression by SM is gene specific, it is unknown whether SM binds to mRNA in a specific manner or whether its RNA binding is target independent. SM-mRNA complexes were isolated from EBVinfected B-lymphocyte cell lines induced to permit lytic EBV replication, and a quantitative measurement of mRNAs corresponding to all known EBV open reading frames was performed by real-time quantitative reverse transcription-PCR. The results showed that although SM has broad RNA binding properties, there is a clear hierarchy of affinities among EBV mRNAs with respect to SM complex formation. In vitro binding assays with two of the most highly SM-associated transcripts suggested that SM binds preferentially to specific sequences or structures present in noncoding regions of some EBV mRNAs. Furthermore, the presence of these sequences conferred responsiveness to SM. These data are consistent with a mechanism of action similar to that of hnRNPs, which exert sequence-specific effects on gene expression despite having multiple degenerate consensus binding sites common to a large number of RNAs.Epstein-Barr virus (EBV) SM is an RNA binding protein that is essential for lytic EBV replication (1,5,6,8,14,15,17,(33)(34)(35)42). The SM gene is homologous to immediate-early or early genes expressed by several other human and animal herpesviruses, including those encoding herpes simplex virus type 1 (HSV-1) ICP27, human cytomegalovirus (HCMV) UL69, varicella-zoster virus open reading frame 4 (ORF4) protein, and Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 protein/Mta (2,24,27,30,36,47). These proteins are multifunctional and function as transcriptional and posttranscriptional regulators of gene expression. One of the major roles of SM is to enhance EBV gene expression by increasing the accumulation of lytic EBV transcripts (5, 21, 39). In experiments performed with cells infected with recombinant EBV with SM deleted, exogenous expression of SM increased the expression of more than 50% of lytic EBV transcripts (15). Most of these SM-responsive transcripts accumulate poorly in the absence of SM. The dependence of these mRNAs on SM is multifactorial, as lytic EBV DNA replication also requires SM, primarily due to SM-enhanced expression of EBV DNA polymerase and primase proteins (15). Thus, SM may stimulate lytic EBV gene expression indirectly, by enhancing lytic EBV replication, as well as by having direct effects on target mRNAs. SM is thought to bind to EBV mRNAs in the nucleus and to enhance mRNA e...

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“…In addition, it has been shown that PML-NBs have role in the repression of HSV-1 infection in the absence of functional ICP0 and they may be involved in regulating lytic and latent infection of HSV-1 (Wang et al, 2012). PML-NB protein has been shown to interact with the EBV protein SM and increase the stability of lytic EBV transcripts (Nicewonger et al, 2004). In addition, PML has been among three hub genes identified by Network analysis showing significant differential expression between EBV positive and negative post-transplant lymphoproliferative disorder (PTLD).…”

Section: 8019 Promyelocytic Leukemia Gene Functions and Roles In Tummentioning

confidence: 99%

Promyelocytic Leukemia Gene Functions and Roles in Tumorigenesis

Imani-Saber

Ghafouri‐Fard²

2014

Asian Pacific Journal of Cancer Prevention

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Epstein-Barr Virus (EBV) SM Protein Induces and Recruits Cellular Sp110b To Stabilize mRNAs and Enhance EBV Lytic Gene Expression

Cited by 60 publications

References 46 publications

Negative Autoregulation of Epstein-Barr Virus (EBV) Replicative Gene Expression by EBV SM Protein

Negative Autoregulation of Epstein-Barr Virus (EBV) Replicative Gene Expression by EBV SM Protein

General and Target-Specific RNA Binding Properties of Epstein-Barr Virus SM Posttranscriptional Regulatory Protein

Promyelocytic Leukemia Gene Functions and Roles in Tumorigenesis

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