Emerging Themes from EBV and KSHV microRNA Targets

Ramalingam, Dhivya; Kieffer-Kwon, Philippe; Ziegelbauer, Joseph M.

doi:10.3390/v4091687

Cited by 55 publications

(49 citation statements)

References 81 publications

(145 reference statements)

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“…For example, both host and viral miRNAs have been implicated in the adaptive and innate immune responses, cell death, and tumorigenesis (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). miRNAs are generally derived from primary transcripts that are processed by the Microprocessor complex (comprised of the endonuclease Drosha and its binding partner, DGCR8) that give rise to the ϳ65-nucleotide hairpin precursor miRNA (pre-miRNA) (15)(16)(17)(18).…”

mentioning

confidence: 99%

Naturally Arising Strains of Polyomaviruses with Severely Attenuated MicroRNA Expression

Chen¹,

Kincaid²,

Azarm³

et al. 2014

J Virol

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Several different polyomaviruses (PyVs) encode microRNAs (miRNAs) that regulate viral as well as host gene expression. However, the functions of polyomaviral miRNAs, particularly during in vivo infection, remain poorly understood. Here we identify rare naturally arising PyVs that are severely attenuated or null for miRNA expression. We identify hypomorphic or null strains for miRNA expression from rhesus macaque simian virus 40 (SV40) and human JC virus. These strains were isolated from immunocompromised hosts and derive from insertions or deletions in the viral DNA that preserve the amino acid reading frame of opposing-strand large T antigen gene. Characterization of the SV40 miRNA hypomorph, K661, shows that it is inhibited at the early miRNA biogenesis step of Drosha-mediated processing. Despite having a nonrearranged enhancer, which a previous study has shown renders some PyVs more susceptible to the autoregulatory activities of the miRNA, restoring miRNA expression to K661 has little effect on virus growth in either immortalized or primary monkey kidney cells. Thus, in addition to any effect of accompanying genomic elements, these results suggest that the cellular context also determines susceptibility to PyV miRNAmediated effects. Combined, these results demonstrate that polyomaviruses lacking miRNAs can arise infrequently and that the functional importance of polyomaviral miRNAs is context dependent, consistent with an activity connected to the immune status of the host. IMPORTANCEDiverse virus families encode miRNAs, yet much remains unknown about viral miRNA function and contribution to the infectious cycle. Polyomaviruses (PyVs) are small DNA viruses, long known to be important as etiological agents of rare diseases and valuable models of DNA virus infection. Here, in immunosuppressed hosts, we uncover rare naturally arising variants of different PyVs that have lost the ability to express miRNAs. This represents some of the only known natural viruses to have lost miRNA expression. By probing the biogenesis pathways of these variants, we uncover that miRNA expression is lost via small insertions or deletions that render the transcripts resistant to early steps of miRNA biogenesis while preserving the reading frame of the opposing T antigen transcripts. Overall, our study informs how miRNA genes evolve/devolve in viruses and suggests that miRNA function is exquisitely dependent not only on viral genomic context but also on the cellular and host environment.

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confidence: 99%

Naturally Arising Strains of Polyomaviruses with Severely Attenuated MicroRNA Expression

Chen¹,

Kincaid²,

Azarm³

et al. 2014

J Virol

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“…In PEL cells, proteins expressed from the latent genes are responsible for the maintenance of the episomal KSHV genome, inhibition of tumor suppressor p53, cell cycle regulation, inhibition of apoptosis, host gene regulation, stabilization of cytokine expression, antiapoptosis, antiautophagy, immune evasion, and proliferation (11)(12)(13)(14)(15)(16)(17)(18). In addition, KSHV latency-associated microRNAs are also involved in cell survival (19,20), and recently miR-K12-11 has been shown to promote B-cell expansion in vivo (21).…”

mentioning

confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus-Positive Primary Effusion Lymphoma Tumor Formation in NOD/SCID Mice Is Inhibited by Neomycin and Neamine Blocking Angiogenin's Nuclear Translocation

Bottero

Sadagopan

Johnson

et al. 2013

J Virol

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“…KSHV-infected B lymphoma cell lines generally express latency associated viral transcripts including viral miRs [14]. While BC-1 is dually-infected with KSHV and EBV [15], BCBL-1 is infected by KSHV alone [16].…”

Section: Resultsmentioning

confidence: 99%

Viral oncomiR spreading between B and T cells is employed by Kaposi's sarcoma herpesvirus to induce non-cell-autonomous target gene regulation

et al. 2016

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The two human lymphotrophic γ-herpesviruses, Kaposi's sarcoma herpesvirus (KSHV) and Epstein-Barr virus (EBV), are a recognized cause of human cancer, encoding multiple miRs that are major players in carcinogenesis. Previously, we discovered that EBV-encoded miRs transfer between infected B and T lymphocytes. To further explore the biological significance of the spreading of γ-herpesvirus-encoded miRs on carcinogenesis, we focused on KSHV-miR-K12-11 (miR-K12-11) that is unique in having an identical seed sequence with the oncomiR hsa-miR-155, implicated in B cell lymphomas development. Here, we show for the first time that miR-K12-11 transfers in vitro from KSHV-infected BCBL-1 and BC-1 lymphoma lines to T cells. The transferred miR-K12-11 is active in the adopting T cells and binds its canonical target, the 3′-UTR of BACH1. Importantly, we show that the transfer of miR-K12-11 from BCBL-1 to Jurkat cells correlates with inhibition of the innate type-I interferons response to viral dsRNAs downstream of IKKε, a validated miR-K12-11 target. Finally, we show that miR-K12-11 spreading is not reduced by blocking the classical ceramide-dependent exosome secretion pathway. In summary, we report for the first time that intercellular viral oncomiR spreading is an additional mechanism employed by KSHV to inhibit host anti-viral immunity and consequently promote oncogenesis.

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Emerging Themes from EBV and KSHV microRNA Targets

Cited by 55 publications

References 81 publications

Naturally Arising Strains of Polyomaviruses with Severely Attenuated MicroRNA Expression

Naturally Arising Strains of Polyomaviruses with Severely Attenuated MicroRNA Expression

Kaposi's Sarcoma-Associated Herpesvirus-Positive Primary Effusion Lymphoma Tumor Formation in NOD/SCID Mice Is Inhibited by Neomycin and Neamine Blocking Angiogenin's Nuclear Translocation

Viral oncomiR spreading between B and T cells is employed by Kaposi's sarcoma herpesvirus to induce non-cell-autonomous target gene regulation

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