Viral miRNA targeting of bicistronic and polycistronic transcripts

Zhu, Ying; Huang, Yufei; Jung, Jae U.; Liu, Chun; Gao, Shou‐Jiang

doi:10.1016/j.coviro.2014.04.004

Cited by 13 publications

(15 citation statements)

References 84 publications

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“…More than half of all KSHV ORFs are carried on polycistronic transcripts, Ͼ25% of all ORFs are carried by spliced mRNAs, and a few transcripts share promoters and/or pA signals (13,21,59,60,78,79). The ALT lncRNA is coterminal with the bicistronic mRNA K14-ORF74 and includes the K14 and ORF74 CDS, but it is expected that K14 and ORF74 proteins are not translated from ALT, as these ORFs are Ͼ8 kb downstream of the ALT TSS.…”

Section: Discussionmentioning

confidence: 99%

“…However, as microRNAs regulate gene expression by targeting 3= UTRs for downregulation or degradation (79), the 3= UTR common to ALT and the K14-ORF74 mRNA is likely subject to similar microRNA regulation. Some human miRNAs can downregulate the 3= UTRs for K14 and ORF74 in latent PEL cells (60), and it is possible that these microRNAs have the same effect on ALT.…”

Section: Discussionmentioning

confidence: 99%

“…Some human miRNAs can downregulate the 3= UTRs for K14 and ORF74 in latent PEL cells (60), and it is possible that these microRNAs have the same effect on ALT. It is speculated that grouping specific genes into bi-or polycistronic transcripts allows KSHV to maximize its coding capacity and level of gene regulation (78,79). For example, splicing of one bicistronic mRNA that disrupts a large portion of the upstream ORF allows expression of the downstream protein (80).…”

Section: Discussionmentioning

confidence: 99%

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Expression of the Antisense-to-Latency Transcript Long Noncoding RNA in Kaposi's Sarcoma-Associated Herpesvirus

Schifano

Corcoran

Kelkar

et al. 2017

J Virol

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The regulation of latency is central to herpesvirus biology. Recent transcriptome-wide surveys have uncovered evidence for promiscuous transcription across the entirety of the Kaposi's sarcoma-associated herpesvirus (KSHV) genome and postulated the existence of multiple viral long noncoding RNAs (lncRNAs). Nextgeneration sequencing studies are highly dependent on the specific experimental approach and particular algorithms of analysis and therefore benefit from independent confirmation of the results. The antisense-to-latency transcript (ALT) lncRNA was discovered by genome-tiling microarray (Chandriani et al., J Virol 86:7934 -7942, 2010, https://doi.org/10.1128/JVI.00645-10). To characterize ALT in detail, we physically isolated this lncRNA by a strand-specific hybrid capture assay and then employed transcriptome sequencing and novel reverse transcription-PCR (RT-PCR) assays to distinguish all RNA species in the KSHV latency region. These methods confirm that ALT initiates at positions 120739/121012 and encodes a single splice site, which is shared with the 3=-coterminal K14-vGPCR/ORF74 mRNA, terminating at 130873 (GenBank accession number GQ994935), resulting in an ϳ10,000-nucleotide transcript. No shorter ALT isoforms were identified. This study also identified a novel intron within the LANA 5= untranslated region using a splice acceptor at 127888. In summary, ALT joins PAN/nut1/T1.1 as a bona fide lncRNA of KSHV with potentially important roles in viral gene regulation and pathogenesis.IMPORTANCE Increasing data support the importance of noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and lncRNAs, which have been shown to exert critical regulatory functions without coding for recognizable proteins. Defining the sequences of these ncRNAs is essential for future studies aiming to functionally characterize a specific ncRNA. Most lncRNA studies are highly dependent on high-throughput sequencing and bioinformatic analyses, few studies follow up on the initial predictions, and analyses are at times discordant. The manuscript characterizes one key viral lncRNA, ALT, by physically isolating ALT and by a sequencing-independent assay. It provides for a simple assay to monitor lncRNA expression in experimental and clinical samples. ALT is expressed antisense to the major viral latency transcripts encoding LANA as well as the viral miRNAs and thus has the potential to regulate this key part of the viral life cycle.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Expression of the Antisense-to-Latency Transcript Long Noncoding RNA in Kaposi's Sarcoma-Associated Herpesvirus

Schifano

Corcoran

Kelkar

et al. 2017

J Virol

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“…KSHV encodes over 115 genes including 25 miRNAs [6]. However, the roles of most of these genes, particularly the viral miRNAs, in KSHV biology and pathogenesis remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…During latent infection, KSHV also expresses 12 pre-microRNAs (pre-miRNAs) that are processed to yield 25 mature miRNAs [6]. Mature miRNAs are approximately 22 nucleotides long, single-stranded non-coding RNAs that bind to mRNAs, resulting in their degradation and/or translational repression [7, 8].…”

Section: Introductionmentioning

confidence: 99%

Kaposi's sarcoma herpesvirus (KSHV) microRNA K12-1 functions as an oncogene by activating NF-κB/IL-6/STAT3 signaling

et al. 2016

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The human oncogenic virus Kaposi's sarcoma herpesvirus (KSHV) is the most common cause of malignancies among AIDS patients. KSHV possesses over hundred genes, including 25 microRNAs (miRNAs). The roles of these miRNAs and many other viral genes in KSHV biology and pathogenesis remain largely unknown. Accordingly, the molecular mechanisms by which KSHV induces tumorigenesis are still poorly defined. Here, we identify KSHV miRNA K12-1 (miR-K12-1) as a novel viral oncogene by activating two important transcription factors, nuclear factor-κb (NF-κB) and signal transducer and activator of transcription 3 (STAT3). Interestingly, miR-K12-1 activates STAT3 indirectly through inducing NF-κB activation and NF-κB-dependent expression of the cytokine interleukin-6 (IL-6) by repressing the expression of the NF-κB inhibitor IκBα. Accordingly, expression of ectopic IκBα or knockdown of NF-κB RelA, IL-6 or STAT3 prevents expression of cell growth genes and suppresses the oncogenicities of both miR-K12-1 and KSHV. These data identify miR-K12-1/NF-κB/IL-6/STAT3 as a novel oncogenic signaling underlying KSHV tumorigenesis. These data also provide the first evidence showing that IL-6/STAT3 signaling acts as an essential mediator of NF-κB oncogenic actions. These findings significantly improve our understanding of KSHV pathogenesis and oncogenic interaction between NF-κB and STAT3.

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SIRT1 and AMPK pathways are essential for the proliferation and survival of primary effusion lymphoma cells

Tan

Vasan

et al. 2017

The Journal of Pathology

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Primary effusion lymphoma (PEL) is a rare and aggressive B-cell lymphoma with a dismal prognosis caused by infection of Kaposi’s sarcoma-associated herpesvirus. Despite the findings that numerous viral genes and cellular pathways are essential for the proliferation and survival of PEL cells, there is currently no effective therapeutic treatment for PEL. Here, we report that the metabolic sensor SIRT1 is functionally required for sustaining the proliferation and survival of PEL cells. Knockdown of SIRT1 with specific shRNAs or inhibition of SIRT1 with an inhibitor (Tenovin-6) induced cell cycle arrest and apoptosis in PEL cells. We detected high levels of AMPK activation in PEL cells; reflected in AMPKα1 phosphorylation at T174. Knockdown or inhibition of SIRT1 reduced AMPK activation, indicating that SIRT1 was required for AMPK activation. Interestingly, knockdown of AMPK with specific shRNAs or inhibition of AMPK with the inhibitor Compound C recapitulated the phenotype of SIRT1, and induced cell cycle arrest and apoptosis, whereas overexpression of a constitutively-active AMPK construct rescued the cytotoxic effect of SIRT1 knockdown. Remarkably, treatment with Tenovin-6 effectively inhibited the initiation and progression of PEL, and significantly extended the survival of mice in a murine PEL model. Taken together, these results illustrate that the SIRT1-AMPK axis is essential for maintaining the proliferation and survival of PEL, identify SIRT1 and AMPK as potential therapeutic targets, and Tenovin-6 as a candidate therapeutic agent for PEL patients.

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Viral miRNA targeting of bicistronic and polycistronic transcripts

Cited by 13 publications

References 84 publications

Expression of the Antisense-to-Latency Transcript Long Noncoding RNA in Kaposi's Sarcoma-Associated Herpesvirus

Expression of the Antisense-to-Latency Transcript Long Noncoding RNA in Kaposi's Sarcoma-Associated Herpesvirus

Kaposi's sarcoma herpesvirus (KSHV) microRNA K12-1 functions as an oncogene by activating NF-κB/IL-6/STAT3 signaling

SIRT1 and AMPK pathways are essential for the proliferation and survival of primary effusion lymphoma cells

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