Epstein-Barr Virus–Encoded miR-BART20-5p Inhibits T-bet Translation with Secondary Suppression of p53 in Invasive Nasal NK/T-Cell Lymphoma

Lin, Ting-Chu; Liu, Ting-Yun; Hsu, Su-Ming; Lin, Chao-Wen

doi:10.1016/j.ajpath.2013.01.025

Cited by 41 publications

(42 citation statements)

References 39 publications

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“…Previously, miR-BART20-5p has been shown to target Tbet, the master transcription factor for cytotoxic natural killer (NK) cells, resulting in secondary suppression of p53 in NNL (53). Recently, miR-BART20-5p was shown to target IFNG (gamma interferon [IFN-␥]) as well (54).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, miR-BART20-5p was shown to target IFNG (gamma interferon [IFN-␥]) as well (54). On the basis of these results, an association between invasive NNL pathogenesis and the inhibition of T-bet and IFNG (IFN-␥) by miR-BART20-5p has been suggested (53,54). Thus, miR-BART20-5p inhibitors may induce T-bet, IFNG (IFN-␥), and p53 expression as well as EBV lytic antigens in EBV-associated tumors.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA miR-BART20-5p Stabilizes Epstein-Barr Virus Latency by Directly Targeting BZLF1 and BRLF1

Jung

Choi

Kim

et al. 2014

J Virol

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Epstein-Barr virus (EBV) is a human herpesvirus associated with various tumors. Rather than going through the lytic cycle, EBV maintains latency by limiting the expression of viral genes in tumors. Viral microRNAs (miRNAs) of some herpesviruses have been reported to directly target immediate early genes and suppress lytic induction. In this study, we investigated whether BamHI-A rightward transcript (BART) miRNAs targeted two EBV immediate early genes, BZLF1 and BRLF1. Bioinformatic analysis predicted that 12 different BART miRNAs would target BRLF1. Of these, the results of a luciferase reporter assay indicated that only one interacted with the 3= untranslated region (UTR) of BRLF1: miR-BART20-5p. miR-BART20-5p's effect on gene expression involved two putative seed match sites in the BRLF1 3= UTR, but a mutant version of the miRNA, miR-BART20-5pm, had no effect on expression. As expected from the fact that the entire 3= UTR of BZLF1 resides within the 3= UTR of BRLF1, miR-BART20-5p interacted with the 3= UTR of BZLF1 as well. BZLF1 and BRLF1 mRNA and protein expression was suppressed in cells of an AGS cell line infected with the recombinant Akata strain of EBV (AGS-EBV) transfected with a miR-BART20-5p mimic. The expression of various EBV early proteins was also suppressed by the miR-BART20-5p mimic. In contrast, BZLF1 and BRLF1 expression in AGS-EBV cells transfected with a miR-BART20-5p inhibitor was enhanced. Furthermore, progeny virus production was suppressed by the miR-BART20-5p mimic and enhanced by the miR-BART20-5p inhibitor in AGS-EBV cells induced for the lytic cycle. Our data suggest that miR-BART20-5p plays a key role in latency maintenance in EBV-associated tumors by directly targeting immediate early genes. IMPORTANCEHerpesviruses maintain latency using various mechanisms and establish lifelong infection in the host. From time to time, herpesviruses are reactivated and express immediate early genes which trigger a lytic cascade, leading to the production of progeny viruses. Recently, some herpesviruses have been shown to use their own microRNAs (miRNAs) to downregulate immediate early genes to inhibit the lytic cycle. This study presents evidence that EBV also downregulates two immediate early genes by miR-BART20-5p to suppress the lytic cycle and progeny virus production. Overall, this is the first study to report the direct regulation of EBV immediate early genes by an EBV miRNA, implying its likely importance in latency maintenance in EBV-associated tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MicroRNA miR-BART20-5p Stabilizes Epstein-Barr Virus Latency by Directly Targeting BZLF1 and BRLF1

Jung

Choi

Kim

et al. 2014

J Virol

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“…An increasing number of studies have found BARTs to contribute to immune evasion by targeting cellular factors related to the immune system. BART20-5p targets TBX21/T-bet, leading to decreased IFN-γ production, IL-2, and Th2 cytokine production [19] . BART15-3p targets NLRP3 and subsequently inhibits NLRP3 inflammasome activation and IL-1β cytokine production [42] .…”

Section: Discussionmentioning

confidence: 99%

“…Several BART microRNAs have been involved in the host immune response and became a strategy employed by EBV for immune evasion during EBV infection [16] . For instance, BART20-5p, BART2-5p, and BART3 are involved in immune evasion by targeting TBX21/T-bet, MICB, and IPO7, respectively [17][18][19] . However, the roles of BART microRNAs in regulating host immune responses are still unclear.…”

Section: Introductionmentioning

confidence: 99%

Epstein-Barr Virus miR-BART6-3p Inhibits the RIG-I Pathway

Lu¹,

Qin²,

Jia³

et al. 2017

J Innate Immun

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Recognition of viral pathogen-associated molecular patterns by pattern recognition receptors (PRRs) is the first step in the initiation of a host innate immune response. As a PRR, RIG-I detects either viral RNA or replication transcripts. Avoiding RIG-I recognition is a strategy employed by viruses for immune evasion. Epstein-Barr virus (EBV) infects the majority of the human population worldwide. During the latent infection period there are only a few EBV proteins expressed, whereas EBV-encoded microRNAs, such as BART microRNAs, are highly expressed. BART microRNAs regulate both EBV and the host's gene expression, modulating virus proliferation and the immune response. Here, through gene expression profiling, we found that EBV miR-BART6-3ps inhibited genes of RIG-I-like receptor signaling and the type I interferon (IFN) response. We demonstrated that miR-BART6-3p rather than other BARTs specifically suppressed RIG-I-like receptor signaling-mediated IFN-β production. RNA-seq was used to analyze the global transcriptome change upon EBV infection and miR-BART6-3p mimics transfection, which revealed that EBV infection-triggered immune response signaling can be repressed by miR-BART6-3p overexpression. Furthermore, miR-BART6-3p inhibited the EBV-triggered IFN-β response and facilitated EBV infection through targeting the 3′UTR of RIG-I mRNA. These findings provide new insights into the mechanism underlying the strategies employed by EBV to evade immune surveillance.

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“…A stem-loop RT-PCR for miRNAs was performed according to a published protocol with modification. 20,21 For RT, the reverse primers were: For PCR, an universal reverse PCR primer, 5 0 -TGGCAGGGTCCGAGGT-3 0 , and miRNA-specific forward primers were used. The specific forward primers were: 5 0 -GGGTAACACTGTCTGGTAA-3 0 for miR-200a, 5 0 -GGGTAATACTGCCTGGTAA-3 0 for miR-200b, and 5 0 -GGGTAATACTGCCGGGTAAT-3 0 for miR-200 c. Real-time PCRs were carried out in a 20-ml reaction mixture that included 5 ml diluted cDNA, 0.1 mM miRNA-specific forward primer, 0.1 mM universal reverse primer, and 10 ml of SYBR Green PCR master mix (TOYOBO, Tokyo, Japan).…”

Section: Bioinformaticsmentioning

confidence: 99%

Inhibition of ZEB1 by miR-200 characterizes Helicobacter pylori-positive gastric diffuse large B-cell lymphoma with a less aggressive behavior

et al. 2014

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Primary gastric diffuse large B-cell lymphomas may or may not have a concurrent component of mucosaassociated lymphoid tissue lymphoma. Diffuse large B-cell lymphoma/mucosa-associated lymphoid tissue lymphomas are often associated with Helicobacter pylori (H. pylori) infection, suggesting that the large cells are transformed from mucosa-associated lymphoid tissue lymphomas. In contrast, only limited data are available on the clinical and molecular features of pure gastric diffuse large B-cell lymphomas. In 102 pure gastric diffuse large B-cell lymphomas, we found H. pylori infection in 53% of the cases. H. pylori-positive gastric diffuse large B-cell lymphomas were more likely to present at an earlier stage (73% vs 52% at stage I/II, P ¼ 0.03), to achieve complete remission (75% vs 43%, P ¼ 0.001), and had a better 5-year disease-free survival rate (73% vs 29%, Po0.001) than H. pylori-negative gastric diffuse large B-cell lymphomas. Through genome-wide expression profiles of both miRNAs and mRNAs in nine H. pylori-positive and nine H. pylori-negative gastric diffuse large B-cell lymphomas, we identified inhibition of ZEB1 (zinc-finger E-box-binding homeobox 1) by miR-200 in H. pylori-positive gastric diffuse large B-cell lymphomas. ZEB1, a transcription factor for marginal zone B cells, can suppress BCL6, the master transcription factor for germinal center B cells. In 30 H. pylori-positive and 30 H. pylori-negative gastric diffuse large B-cell lymphomas, we confirmed that H. pylori-positive gastric diffuse large B-cell lymphomas had higher levels of miR-200 by qRT-PCR, and lower levels of ZEB1 and higher levels of BCL6 using immunohistochemistry. As BCL6 is a known predictor of a better prognosis in gastric diffuse large B-cell lymphomas, our data demonstrate that inhibition of ZEB1 by miR-200, with secondary increase in BCL6, is a molecular event that characterizes H. pylori-positive gastric diffuse large B-cell lymphomas with a less aggressive behavior.

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Epstein-Barr Virus–Encoded miR-BART20-5p Inhibits T-bet Translation with Secondary Suppression of p53 in Invasive Nasal NK/T-Cell Lymphoma

Cited by 41 publications

References 39 publications

MicroRNA miR-BART20-5p Stabilizes Epstein-Barr Virus Latency by Directly Targeting BZLF1 and BRLF1

MicroRNA miR-BART20-5p Stabilizes Epstein-Barr Virus Latency by Directly Targeting BZLF1 and BRLF1

Epstein-Barr Virus miR-BART6-3p Inhibits the RIG-I Pathway

Inhibition of ZEB1 by miR-200 characterizes Helicobacter pylori-positive gastric diffuse large B-cell lymphoma with a less aggressive behavior

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