Bovine Leukemia Virus Small Noncoding RNAs Are Functional Elements That Regulate Replication and Contribute to Oncogenesis In Vivo

Gillet, Nicolas; Hamaïdia, Malik; Brogniez, Alix de; Gutiérrez, Gerónimo; Renotte, Nathalie; Reichert, M.; Trono, K.; Willems, Luc

doi:10.1371/journal.ppat.1005588

Cited by 53 publications

(58 citation statements)

References 39 publications

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“…115 However, no proof of concept has been shown, nor has preliminary data been published concerning the identity of the provirus mutated/deleted genes, the immune protection conferred to the vaccinated animals in the long term, the safety assessment of the vaccine, and the proposed strategy to be used to differentiate vaccinated from infected animals. The recent evidence on the role of viral miRNA in BLV pathogenesis 14 together with the finding that BLV proviruses are integrated near cancer drivers, whose expression is perturbed by the integrated proviruses, 16 further emphasizes the need of caution on retroviral live-attenuated vaccines. It should also be borne in mind that the use of an attenuated retroviral vaccine implies a risk for disruption of genes upon insertion into the cellular genome, preventing their expression, and there is also the risk of reversion to virulent, oncogenic forms in the long run.…”

Section: -101mentioning

confidence: 99%

Bovine leukemia virus: current perspectives

Juliarena¹,

Barrios²,

Lützelschwab³

et al. 2017

VAAT

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Enzootic bovine leukosis, caused by bovine leukemia virus (BLV), is the most common neoplasm of dairy cattle. Although beef and dairy cattle are susceptible to BLV infection and BLV-associated lymphosarcoma, the disease is more commonly detected in dairy herds, mostly because of the management practices in dairy farms. The pathogenicity of BLV in its natural host, the bovine, depends mainly on the resistance/susceptibility genetics of the animal. The majority of infected cattle are asymptomatic, promoting the extremely high dissemination rate of BLV in many bovine populations. The important productive losses caused by the BLV, added to the health risk of maintaining populations with a high prevalence of infection with a retrovirus, generates the need to implement control measures. Different strategies to control the virus have been attempted. The most effective approach is to identify and cull the totality of infected cattle in the herd. However, this approach is not suitable for herds with high prevalence of infection. At present, no treatment or vaccine has proven effective for the control of BLV. Thus far, the genetic selection of resistant animals emerges as a natural strategy for the containment of the BLV dissemination. In natural conditions, most of the infected, resistant cattle can control the infection, and therefore do not pass the virus to other animals, gradually decreasing the prevalence of the herd.

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Section: -101mentioning

confidence: 99%

Bovine leukemia virus: current perspectives

Juliarena¹,

Barrios²,

Lützelschwab³

et al. 2017

VAAT

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show abstract

“…To determine whether the lack of DUSP11 affects miRNA-mediated down-regulation of a more biologically relevant target mRNA, we searched for possible target sites of all known isoforms of BLV-miR-B5-5p in bovine transcripts that are at least indirectly targeted by BLV miRNAs during infection of primary peripheral blood mononuclear cells (PBMCs) (Gillet et al 2016). We identified one transcript, CECR1, with four predicted miRNA docking sites for BLV(913)-miR-B5-5p in its 3 ′ UTR.…”

Section: Knockout Of Dusp11 Decreases the Risc Activity Of The Blv 5pmentioning

confidence: 99%

DUSP11 activity on triphosphorylated transcripts promotes Argonaute association with noncanonical viral microRNAs and regulates steady-state levels of cellular noncoding RNAs

et al. 2016

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RNA silencing is a conserved eukaryotic gene expression regulatory mechanism mediated by small RNAs. In Caenorhabditis elegans, the accumulation of a distinct class of siRNAs synthesized by an RNA-dependent RNA polymerase (RdRP) requires the PIR-1 phosphatase. However, the function of PIR-1 in RNAi has remained unclear. Since mammals lack an analogous siRNA biogenesis pathway, an RNA silencing role for the mammalian PIR-1 homolog (dual specificity phosphatase 11 [DUSP11]) was unexpected. Here, we show that the RNA triphosphatase activity of DUSP11 promotes the RNA silencing activity of viral microRNAs (miRNAs) derived from RNA polymerase III (RNAP III) transcribed precursors. Our results demonstrate that DUSP11 converts the 5 ′ triphosphate of miRNA precursors to a 5 ′ monophosphate, promoting loading of derivative 5p miRNAs into Argonaute proteins via a Dicer-coupled 5 ′ monophosphate-dependent strand selection mechanism. This mechanistic insight supports a likely shared function for PIR-1 in C. elegans. Furthermore, we show that DUSP11 modulates the 5 ′ end phosphate group and/or steady-state level of several host RNAP III transcripts, including vault RNAs and Alu transcripts. This study shows that steady-state levels of select noncoding RNAs are regulated by DUSP11 and defines a previously unknown portal for small RNA-mediated silencing in mammals, revealing that DUSP11-dependent RNA silencing activities are shared among diverse metazoans.

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“…MicroRNAs (miRNAs) are small regulatory (~21-24 nucleotide (nt)) non-coding RNAs that are involved in diverse biological processes, including cancer (reviewed in (Di Leva et al, 2014)). Although the non-acute retrovirus bovine leukemia virus (BLV) encodes miRNAs that may contribute to their oncogenic capacity (Gillet et al, 2016; Kincaid et al, 2012), whether MMTV encodes miRNAs is unknown.…”

Section: Introductionmentioning

confidence: 99%

MMTV does not encode viral microRNAs but alters the levels of cancer-associated host microRNAs

et al. 2018

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Mouse mammary tumor virus (MMTV) induces breast cancer in mice in the absence of known virally-encoded oncogenes. Tumorigenesis by MMTV is thought to occur primarily through insertional mutagenesis, leading to the activation of cellular proto-oncogenes and outgrowth of selected cells. Here we investigated whether MMTV encodes microRNAs (miRNAs) and/or modulates host miRNAs that could contribute to tumorigenesis. High throughput small RNA sequencing analysis of MMTV-infected cells and MMTV-induced mammary tumors demonstrates that MMTV does not encode miRNAs. However, infected tissues have altered levels of several host miRNAs, including increased expression of members of the oncogenic miRNA cluster, miR-17-92. Notably, similar changes in miRNA levels have been previously reported in human breast cancers. Combined, our results demonstrate that virally encoded miRNAs do not contribute to MMTV-mediated tumorigenesis, but that changes in specific host miRNAs in infected cells may contribute to virus replication and tumor biology.

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Bovine Leukemia Virus Small Noncoding RNAs Are Functional Elements That Regulate Replication and Contribute to Oncogenesis In Vivo

Cited by 53 publications

References 39 publications

Bovine leukemia virus: current perspectives

Bovine leukemia virus: current perspectives

DUSP11 activity on triphosphorylated transcripts promotes Argonaute association with noncanonical viral microRNAs and regulates steady-state levels of cellular noncoding RNAs

MMTV does not encode viral microRNAs but alters the levels of cancer-associated host microRNAs

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