Epstein-Barr Virus Induces Global Changes in Cellular mRNA Isoform Usage That Are Important for the Maintenance of Latency

Homa, Nicholas J.; Salinas, Raul; Forte, Eleonora; Robinson, Timothy J.; García-Blanco, Mariano A.; Luftig, Micah A.

doi:10.1128/jvi.02464-13

Cited by 13 publications

(11 citation statements)

References 63 publications

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“…3′UTR shortening is known to occur in highly proliferative states such as cancer 37,38 . Furthermore, B cells infected with Epstein-Barr virus (EBV) demonstrate reduced 3′UTR lengths for a number of host transcripts 39 . However, EBV establishes a latent infection and immortalizes B cells, and the altered host polyadenylation patterns appear to be a consequence of the associated proliferation rather than the infection itself 39 .…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, B cells infected with Epstein-Barr virus (EBV) demonstrate reduced 3′UTR lengths for a number of host transcripts 39 . However, EBV establishes a latent infection and immortalizes B cells, and the altered host polyadenylation patterns appear to be a consequence of the associated proliferation rather than the infection itself 39 . However, during lytic HCMV infection, the cells are not proliferative, indicating that global 3′UTR shortening is not a secondary effect of proliferation.…”

Section: Discussionmentioning

confidence: 99%

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RNA-binding protein CPEB1 remodels host and viral RNA landscapes

Batra

Stark

Clark

et al. 2016

Nat Struct Mol Biol

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Host and virus interactions at the post-transcriptional level are critical for infection but remain poorly understood. Human cytomegalovirus (HCMV) is a prevalent herpesvirus family member that causes severe complications in immunocompromised patients and newborns. Here, we perform comprehensive transcriptome-wide analyses revealing that HCMV infection results in widespread alternative splicing (AS), shorter 3′-untranslated regions (3′UTRs) and polyA tail lengthening in host genes. The host RNA binding protein cytoplasmic polyadenylation element binding protein 1 (CPEB1) is highly induced upon infection and ectopic expression of CPEB1 in non-infected cells recapitulates infection-related post-transcriptional changes. CPEB1 is also required for polyA-tail lengthening of viral RNAs important for productive infection. Strikingly, depletion of CPEB1 reverses infection-related cytopathology and post-transcriptional changes, and decreases productive HCMV titers. Host RNA processing is also altered in herpes simplex virus-2 (HSV-2) infected cells, indicating a common theme among herpesvirus infections. Our work is a starting point for therapeutic targeting of host RNA binding proteins in herpesvirus infections.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

RNA-binding protein CPEB1 remodels host and viral RNA landscapes

Batra

Stark

Clark

et al. 2016

Nat Struct Mol Biol

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“…Our data indicate post-transcriptional and and/or post-translational regulation of some genes, like EIF2B4 and UBE2C ( Table 1 and Fig 4C ). To our knowledge, EBER-mediated activation of AKT has not been documented previously even though the PI3K-AKT signaling cascade is a known target of the EBV oncoprotein LMP1 [ 18 , 35 ] and a recent bioinformatics study showed that EBV infection affects alternative splicing [ 53 ]. This apparent redundancy in cell signaling activation mediated by EBER expression and the EBV-encoded oncoprotein LMP1 may explain the lack of effects on EBV transformation potential and latency maintenance observed in the EBER-deletion studies reported previously [ 16 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

Proteomics and Transcriptomics of BJAB Cells Expressing the Epstein-Barr Virus Noncoding RNAs EBER1 and EBER2

et al. 2015

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In Epstein-Barr virus (EBV) latent infection, the EBV-encoded RNAs EBER1 and EBER2 accumulate in the host cell nucleus to ~106 copies. While the expression of EBERs in cell lines is associated with transformation, a mechanistic explanation of their roles in EBV latency remains elusive. To identify EBER-specific gene expression features, we compared the proteome and mRNA transcriptome from BJAB cells (an EBV-negative B lymphoma cell line) stably transfected with an empty plasmid or with one carrying both EBER genes. We identified ~1800 proteins with at least 2 SILAC pair measurements, of which only 8 and 12 were up- and downregulated ≥ 2-fold, respectively. One upregulated protein was PIK3AP1, a B-cell specific protein adapter known to activate the PI3K-AKT signaling pathway, which regulates alternative splicing and translation in addition to its pro-survival effects. In the mRNA-seq data, the mRNA levels for some of the proteins changing in the SILAC data did not change. We instead observed isoform switch events. We validated the most relevant findings with biochemical assays. These corroborated the upregulation of PIK3AP1 and AKT activation in BJAB cells expressing high levels of both EBERs and EBNA1 (a surrogate of Burkitt’s lymphoma EBV latency I) relative to those expressing only EBNA1. The mRNA-seq data in these cells showed multiple upregulated oncogenes whose mRNAs are enriched for 3´-UTR AU-rich elements (AREs), such as ccl3, ccr7, il10, vegfa and zeb1. The CCL3, CCR7, IL10 and VEGFA proteins promote cell proliferation and are associated with EBV-mediated lymphomas. In EBV latency, ZEB1 represses the transcription of ZEBRA, an EBV lytic phase activation factor. We previously found that EBER1 interacts with AUF1 in vivo and proposed stabilization of ARE-containing mRNAs. Thus, the ~106 copies of EBER1 may promote not only cell proliferation due to an increase in the levels of ARE-containing genes like ccl3, ccr7, il10, and vegfa, but also the maintenance of latency, through higher levels of zeb1.

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“…Histone acetylation plays an important role in the switch between the lytic and lysogeny phases by regulating BZLF promoter known as Z. It has been suggested that the balance between recruitment of histone acetyltransferases versus histone deacetylases by transacting factors promotes and decides the switch between latency and lytic reactivation [29]. Viral latency may eventuate in carcinogenesis provided the presence of conducive host (susceptibility factors) and viral (oncogenic latency proteins) exists.…”

Section: Ebv Infection Molecular Interaction and Latencymentioning

confidence: 99%

Breast Cancer as an Epstein-Barr Virus (EBV)-Associated Malignancy

Fessahaye¹,

Ibrahim²

2017

Breast Cancer - From Biology to Medicine

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The Epstein Barr Virus is among the very first oncogenic viruses to be identified as culprits of human malignancies. Its role as an etiologic agent of breast cancer however remains debated despite mounting molecular evidence. In this chapter we address the challenge of multiple molecular etiologies of breast cancer (BC) with emphasis on the Epstein Barr Virus (EBV) as a potential causative agent within a frame work of gene/environment interaction. We also hope to contribute to a critique of the a concept of universal single agent or gene in cancer etiology. In addition to reviewing further reasons of why EBV should be considered a tumor virus, coupling molecular targets at the initiation stage, we examine evidence for the culpability of EBV as oncogenic virus in relation to the genetic and epigenetic events that leads to carcinogenesis of cancer; and the subsequent downstream interaction including genetic and epigenetic modifiers of signaling and molecular function underlying the cancerous phenotype. The TNF family is taken as an example of how the epigenetic reprogramming process, impacts molecular targets and how these combined interplay of molecular events impinges on pathogenesis and malignancy of breast cancer in humans.

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Epstein-Barr Virus Induces Global Changes in Cellular mRNA Isoform Usage That Are Important for the Maintenance of Latency

Cited by 13 publications

References 63 publications

RNA-binding protein CPEB1 remodels host and viral RNA landscapes

RNA-binding protein CPEB1 remodels host and viral RNA landscapes

Proteomics and Transcriptomics of BJAB Cells Expressing the Epstein-Barr Virus Noncoding RNAs EBER1 and EBER2

Breast Cancer as an Epstein-Barr Virus (EBV)-Associated Malignancy

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