Latent infection with Kaposi’s sarcoma-associated herpesvirus enhances retrotransposition of long interspersed element-1

Nakayama, Ryota; Ueno, Yutaka; Ueda, Keiji; Honda, Takeshi

doi:10.1038/s41388-019-0726-5

Cited by 22 publications

(22 citation statements)

References 67 publications

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“…We next sought to detect upregulation of endogenous L1 ASP-driven gene transcripts upon our L1 ASP stimulation. The L1 ASP reportedly upregulates the expression of L1 ORF0, whose product stimulates L1 retrotransposition 12,13 . Real-time RT-PCR specific for L1 ASP-driven ORF0 transcripts revealed that the transcripts were indeed upregulated in sgL1ASP-expressing cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Effects of activation of the LINE-1 antisense promoter on the growth of cultured cells

Honda

Nishimura

Teng

et al. 2020

Sci Rep

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Long interspersed element 1 (LINE-1, or L1) is a retrotransposon that constitutes ~ 17% of the human genome. Although ~ 6000 full-length L1s spread throughout the human genome, their biological significance remains undetermined. The L1 5′ untranslated region has bidirectional promoter activity with a sense promoter driving L1 mRNA production and an antisense promoter (ASP) driving the production of L1-gene chimeric RNAs. Here, we stimulated L1 ASP activity using CRISPR-Cas9 technology to evaluate its biological impacts. Activation of the L1 ASP upregulated the expression of L1 ASP-driven ORF0 and enhanced cell growth. Furthermore, the exogenous expression of ORF0 also enhanced cell growth. These results indicate that activation of L1 ASP activity fuels cell growth at least through ORF0 expression. To our knowledge, this is the first report demonstrating the role of the L1 ASP in a biological context. Considering that L1 sequences are desilenced in various tumor cells, our results indicate that activation of the L1 ASP may be a cause of tumor growth; therefore, interfering with L1 ASP activity may be a potential strategy to suppress the growth.

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Section: Resultsmentioning

confidence: 99%

“…The expression plasmid of dCas9-VP64, pcDNA-Cas9m4-VP64, was provided through Addgene (#47319). For the ORF0 expression, One-Strep-FLAG-tagged ORF0 was cloned into the pCAG plasmid similarly to the previous study 13 . The pCAG plasmid expressing only the One-Strep-FLAG tag was used as a mock vector.…”

Section: Methodsmentioning

confidence: 99%

Effects of activation of the LINE-1 antisense promoter on the growth of cultured cells

Honda

Nishimura

Teng

et al. 2020

Sci Rep

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“…Further investigation will be required for clarifying this point. Intriguingly, we have demonstrated that another oncogenic virus, Kaposi’s sarcoma-associated herpesvirus, can enhance L1 retrotransposition [140], which may highlight the importance of L1 in HBV-mediated oncogenesis.…”

Section: Discussionmentioning

confidence: 99%

Profiling of LINE-1-Related Genes in Hepatocellular Carcinoma

Honda

Rahman

2019

IJMS

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Hepatocellular carcinoma (HCC) is a prime public health concern that accounts for most of the primary liver malignancies in humans. The most common etiological factor of HCC is hepatitis B virus (HBV). Despite recent advances in treatment strategies, there has been little success in improving the survival of HCC patients. To develop a novel therapeutic approach, evaluation of a working hypothesis based on different viewpoints might be important. Long interspersed element 1 (L1) retrotransposons have been suggested to play a role in HCC. However, the molecular machineries that can modulate L1 biology in HBV-related HCC have not been well-evaluated. Here, we summarize the profiles of expression and/or activation status of L1-related genes in HBV-related HCC, and HBV- and HCC-related genes that may impact L1-mediated tumorigenesis. L1 restriction factors appear to be suppressed by HBV infection. Since some of the L1 restriction factors also limit HBV, these factors may be exhausted in HBV-infected cells, which causes de-suppression of L1. Several HBV- and HCC-related genes that interact with L1 can affect oncogenic processes. Thus, L1 may be a novel prime therapeutic target for HBV-related HCC. Studies in this area will provide insights into HCC and other types of cancers.

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“…Real-time RT-PCR was conducted, as described previously, with some modifications (Hayashi et al, 2009; Nishikawa et al, 2018; Nakayama et al, 2019). Briefly, total RNA was extracted from the indicated cells and reverse-transcribed using a Verso cDNA Synthesis Kit (Thermo Fisher Scientific, Waltham, United States) according to the manufacturer’s instruction.…”

Section: Methodsmentioning

confidence: 99%

“…Then, Vero cells were infected with the viruses and incubated at 37°C for 3 days. The virus titers (focus forming units/ml) were determined by immunofluorescence analysis (Nakayama et al, 2019; Yamamoto et al, 2019) using anti-N (HB03) and anti-P (HP062) antibodies.…”

Section: Methodsmentioning

confidence: 99%

A Small Interfering RNA Cocktail Targeting the Nucleoprotein and Large Protein Genes Suppresses Borna Disease Virus Infection

et al. 2019

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Recently, Borna disease virus (BoDV-1)-related fatal encephalitis human cases have been reported, which highlights the potential of BoDV-1 to cause fatal human diseases. To protect the infected brain from lethal damage, it is critical to control BoDV-1 as quickly as possible. At present, antivirals against BoDV-1 are limited, and therefore, novel types of antivirals are needed. Here, we developed a novel treatment using small interfering RNAs (siRNAs) against BoDV-1. We screened several siRNAs targeting the viral N, M, and L genes for BoDV-1-reducing activity. Among the screened candidates, we chose two siRNAs that efficiently decreased the BoDV-1 load in persistently BoDV-1-infected cells to prepare a siRNA cocktail (TD-Borna) for BoDV-1 treatment. TD-Borna successfully reduced the BoDV-1 load without enhancing the risk of emergence of escape mutants. The combination of TD-Borna and T-705, a previously reported antiviral agent against bornaviruses, decreased the BoDV-1 load more efficiently than TD-Borna or T-705 alone. Furthermore, TD-Borna efficiently decreased the BoDV-1 load in BoDV-1-infected neuron-derived cells, in which T-705 did not decrease the viral load. Overall, we developed a novel antiviral candidate against BoDV-1, TD-Borna, that can be used in combination with T-705 and is effective against BoDV-1 in neuron-derived cells, in which T-705 is less effective. Considering that BoDV-1 is highly neurotropic, TD-Borna can offer a promising option to improve the outcome of BoDV-1 infection.

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Latent infection with Kaposi’s sarcoma-associated herpesvirus enhances retrotransposition of long interspersed element-1

Cited by 22 publications

References 67 publications

Effects of activation of the LINE-1 antisense promoter on the growth of cultured cells

Effects of activation of the LINE-1 antisense promoter on the growth of cultured cells

Profiling of LINE-1-Related Genes in Hepatocellular Carcinoma

A Small Interfering RNA Cocktail Targeting the Nucleoprotein and Large Protein Genes Suppresses Borna Disease Virus Infection

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