Evolutionary Conservation of Primate Lymphocryptovirus MicroRNA Targets

Skalsky, Rebecca L.; Kang, Dong Woo; Linnstaedt, Sarah D.; Cullen, Bryan R.

doi:10.1128/jvi.02071-13

Cited by 51 publications

(120 citation statements)

References 82 publications

(152 reference statements)

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“…Viral miRNAs have generated excitement, in part, as a previously unrecognized class of gene products that could contribute to understanding the mechanisms of viral disease. Biochemical cross-linking studies have identified direct transcript targets of miRNAs and have provided much insight into viral miRNA biology (6)(7)(8)(9). However, there remain many unanswered important questions.…”

mentioning

confidence: 99%

RETRACTED: Pan-viral-microRNA screening identifies interferon inhibition as a common function of diverse viruses

Cox

McClure

Goga

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Diverse viruses encode regulatory RNAs called microRNAs (miRNAs). Despite much progress, the functions of the majority of viral miRNAs remain unknown. Most previous studies have used biochemical methods to uncover targets of viral miRNAs, but it is unclear what fraction of these targets is functionally important. Here, we apply an alternative strategy based on the premise that assorted viral miRNAs will share functionality. Screening a library of >70 human viral miRNAs showed that three unrelated miRNAs from distantly related herpesviruses significantly inhibited IFN signaling. Strikingly, each of these miRNAs directly reduced expression of the cyclic AMP-responsive element-binding protein (CBP), which as part of the p300-CBP complex, mediates IFN signaling. We show that both 5′ and 3′ derivatives from Epstein–Barr virus (EBV) encoded miR-BART-18 precursor miRNA (pre-miRNA) and the orthologous pre-miRNA from Rhesus lymphocryptovirus contribute to reducing IFN signaling. Thus, through both convergent and divergent evolutionary mechanisms, varied herpesviral miRNAs share the ability to decrease IFN signaling. Restoring miR-BART-18 to cells infected with an EBV miRNA mutant conveyed a cellular growth advantage upon IFN treatment, and relevant miRNAs from other herpesviruses were able to complement this activity. Blocking miR-BART-18 function in an EBV+ tumor cell line renders cells more susceptible to IFN-mediated effects. These findings provide a mechanism that can at least partially explain the resistance of some EBV-associated tumors to IFN therapy. Our work suggests that similar pan-viral-miRNA functional-based screening strategies are warranted for determining relevant activities of other viral miRNAs.

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mentioning

confidence: 99%

RETRACTED: Pan-viral-microRNA screening identifies interferon inhibition as a common function of diverse viruses

Cox

McClure

Goga

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Therefore, to identify EBV miR-BART miRNAs with anti-apoptotic potential, we decided to express each of the 22 miR-BARTs at approximately physiological levels using lentiviral miRNA expression vectors, constructed as previously reported by inserting the entire pri-miR stem-loop, together with ~100 bp of 5’ and 3’ flanking sequence, into the 3’ UTR of the turbo red fluorescent protein (turboRFP) gene present in pTRIPZ [29, 30]. After selection for the included puromycin marker, the cells were sorted for high turboRFP expression (upper 30%) and expanded.…”

Section: Resultsmentioning

confidence: 99%

EBV BART MicroRNAs Target Multiple Pro-apoptotic Cellular Genes to Promote Epithelial Cell Survival

2015

Self Cite

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Epstein-Barr virus (EBV) is a ubiquitous human γ-herpesvirus that can give rise to cancers of both B-cell and epithelial cell origin. In EBV-induced cancers of epithelial origin, including nasopharyngeal carcinomas (NPCs) and gastric carcinomas, the latent EBV genome expresses very high levels of a cluster of 22 viral pre-miRNAs, called the miR-BARTs, and these have previously been shown to confer a degree of resistance to pro-apoptotic drugs. Here, we present an analysis of the ability of individual miR-BART pre-miRNAs to confer an anti-apoptotic phenotype and report that five of the 22 miR-BARTs demonstrate this ability. We next used photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) to globally identify the mRNA targets bound by these miR-BARTs in latently infected epithelial cells. This led to the identification of ten mRNAs encoding pro-apoptotic mRNA targets, all of which could be confirmed as valid targets for the five anti-apoptotic miR-BARTs by indicator assays and by demonstrating that ectopic expression of physiological levels of the relevant miR-BART in the epithelial cell line AGS resulted in a significant repression of the target mRNA as well as the encoded protein product. Using RNA interference, we further demonstrated that knockdown of at least seven of these cellular miR-BART target transcripts phenocopies the anti-apoptotic activity seen upon expression of the relevant EBV miR-BART miRNA. Together, these observations validate previously published reports arguing that the miR-BARTs can exert an anti-apoptotic effect in EBV-infected epithelial cells and provide a mechanistic explanation for this activity. Moreover, these results identify and validate a substantial number of novel mRNA targets for the anti-apoptotic miR-BARTs.

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“…Four EBV miRNAs (miR-BART3, miR-BART5, miR-BART16, and miR-BART17) directly target LMP1, and thereby indirectly inhibit surface expression of certain immune coreceptors and adhesion molecules. This helps to alter the balance of LMP1's growth-promoting and pro-apoptotic actions Skalsky et al, 2014;Verhoeven et al, 2016). Unlike the four abovementioned EBV miRNAs, miR-BART9 is involved in maintaining LMP1 mRNA stability in growing T cell lymphomas, though it does not target LMP1 directly .…”

Section: Ebv-encoded Mirnas Regulate the Immune Response By Targetingmentioning

confidence: 99%

An update: Epstein-Barr virus and immune evasion via microRNA regulation

Zuo

Yue

et al. 2017

Virol. Sin.

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Epstein-Barr virus (EBV) is an oncogenic virus that ubiquitously establishes life-long persistence in humans.To ensure its survival and maintain its B cell transformation function, EBV has developed powerful strategies to evade host immune responses. Emerging evidence has shown that microRNAs (miRNAs) are powerful regulators of the maintenance of cellular homeostasis. In this review, we summarize current progress on how EBV utilizes miRNAs for immune evasion. EBV encodes miRNAs targeting both viral and host genes involved in the immune response. The miRNAs are found in two gene clusters, and recent studies have demonstrated that lack of these clusters increases the CD4 + and CD8 + T cell response of infected cells. These reports strongly indicate that EBV miRNAs are critical for immune evasion. In addition, EBV is able to dysregulate the expression of a variety of host miRNAs, which influence multiple immune-related molecules and signaling pathways. The transport via exosomes of EBV-regulated miRNAs and viral proteins contributes to the construction and modification of the inflammatory tumor microenvironment. During EBV immune evasion, viral proteins, immune cells, chemokines, pro-inflammatory cytokines, and pro-apoptosis molecules are involved. Our increasing knowledge of the role of miRNAs in immune evasion will improve the understanding of EBV persistence and help to develop new treatments for EBV-associated cancers and other diseases.

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Evolutionary Conservation of Primate Lymphocryptovirus MicroRNA Targets

Cited by 51 publications

References 82 publications

RETRACTED: Pan-viral-microRNA screening identifies interferon inhibition as a common function of diverse viruses

RETRACTED: Pan-viral-microRNA screening identifies interferon inhibition as a common function of diverse viruses

EBV BART MicroRNAs Target Multiple Pro-apoptotic Cellular Genes to Promote Epithelial Cell Survival

An update: Epstein-Barr virus and immune evasion via microRNA regulation

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