RNA modifications go viral

Gokhale, Nandan S.; Horner, Stacy M.

doi:10.1371/journal.ppat.1006188

Cited by 72 publications

(62 citation statements)

References 34 publications

(48 reference statements)

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“…This report capitalized on a very versatile and agnostic analytical approach to complete a comprehensive survey of RNA PTMs present on viral genomes and total cellular RNA obtained from virus-infected cells. The results exposed for the first time the remarkable dimensions and diversity of the viral epitranscriptome, which far exceed the handful of modifications reported thus far (100,101). Despite the well-established effects of some PTMs on RNA structure and their implication in maintaining cellular homeostasis (3,102), PTMs have been often perceived as mere passengers introduced in a stochastic fashion by the cellular machinery, or as non-specific components of general mechanisms of stress response.…”

Section: Resultsmentioning

confidence: 89%

Positive-sense RNA viruses reveal the complexity and dynamics of the cellular and viral epitranscriptomes during infection

McIntyre

Netzband

Bonenfant

et al. 2018

Nucleic Acids Research

121

142

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More than 140 post-transcriptional modifications (PTMs) are known to decorate cellular RNAs, but their incidence, identity and significance in viral RNA are still largely unknown. We have developed an agnostic analytical approach to comprehensively survey PTMs on viral and cellular RNAs. Specifically, we used mass spectrometry to analyze PTMs on total RNA isolated from cells infected with Zika virus, Dengue virus, hepatitis C virus (HCV), poliovirus and human immunodeficiency virus type 1. All five RNA viruses significantly altered global PTM landscapes. Examination of PTM profiles of individual viral genomes isolated by affinity capture revealed a plethora of PTMs on viral RNAs, which far exceeds the handful of well-characterized modifications. Direct comparison of viral epitranscriptomes identified common and virus-specific PTMs. In particular, specific dimethylcytosine modifications were only present in total RNA from virus-infected cells, and in intracellular HCV RNA, and viral RNA from Zika and HCV virions. Moreover, dimethylcytosine abundance during viral infection was modulated by the cellular DEAD-box RNA helicase DDX6. By opening the Pandora’s box on viral PTMs, this report presents numerous questions and hypotheses on PTM function and strongly supports PTMs as a new tier of regulation by which RNA viruses subvert the host and evade cellular surveillance systems.

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Section: Resultsmentioning

confidence: 89%

Positive-sense RNA viruses reveal the complexity and dynamics of the cellular and viral epitranscriptomes during infection

McIntyre

Netzband

Bonenfant

et al. 2018

Nucleic Acids Research

121

142

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“…Given the diversity of functions reported form 6 A in controlling cellular processes and virus infections [1,22,27], we also sought to evaluate the role of this pathway in mediating ORF50 expression in another widely used KSHV infected cell line of distinct origin, the B cell line TREX-BCBL-1 [52]. Similar to iSLK.219 and iSLK.BAC16 cells, TREX-BCBL-1 cells also contain a dox-inducible copy of ORF50 to boost reactivation.…”

Section: Resultsmentioning

confidence: 99%

N⁶-methyladenosine modification and the YTHDF2 reader protein play cell type specific roles in lytic viral gene expression during Kaposi’s sarcoma-associated herpesvirus infection

Hesser

Karijolich

Dominissini

et al. 2017

Preprint

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Methylation at the N6 position of adenosine (m6A) is a highly prevalent and reversible modification within eukaryotic mRNAs that has been linked to many stages of RNA processing and fate. Recent studies suggest that m6A deposition and proteins involved in the m6A pathway play a diverse set of roles in either restricting or modulating the lifecycles of select viruses. Here, we report that m6A levels are significantly increased in cells infected with the oncogenic human DNA virus Kaposi’s sarcoma-associated herpesvirus (KSHV). Transcriptome-wide m6A-sequencing of the KSHV-positive renal carcinoma cell line iSLK.219 during lytic reactivation revealed the presence of m6A across multiple kinetic classes of viral transcripts, and a concomitant decrease in m6A levels across much of the host transcriptome. However, we found that depletion of the m6A machinery had differential pro- and anti-viral impacts on viral gene expression depending on the cell-type analyzed. In iSLK.219 and iSLK.BAC16 cells the pathway functioned in a pro-viral manner, as depletion of the m6A writer METTL3 and the reader YTHDF2 significantly impaired virion production. In iSLK.219 cells the defect was linked to their roles in the post-transcriptional accumulation of the major viral lytic transactivator ORF50, which is m6A modified. In contrast, although the ORF50 mRNA was also m6A modified in KSHV infected B cells, ORF50 protein expression was instead increased upon depletion of METTL3, or, to a lesser extent, YTHDF2. These results highlight that the m6A pathway is centrally involved in regulating KSHV gene expression, and underscore how the outcome of this dynamically regulated modification can vary significantly between cell types.Author SummaryIn addition to its roles in regulating cellular RNA fate, methylation at the N6 position of adenosine (m6A) of mRNA has recently emerged as a mechanism for regulating viral infection. While it has been known for over 40 years that the mRNA of nuclear replicating DNA viruses contain m6A, only recently have studies began to examine the distribution of this modification across viral transcripts, as well as characterize its functional impact upon viral lifecycles. Here, we apply m6A-sequencing to map the location of m6A modifications throughout the transcriptome of the oncogenic human DNA virus Kaposi’s sarcoma-associated herpesvirus (KSHV). We show that the m6A machinery functions in a cell type specific manner to either promote or inhibit KSHV gene expression. Thus, the KSHV lifecycle is impacted by the m6A pathway, but the functional outcome may depend on cell lineage specific differences in m6A-based regulation.

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“…Wang et al 2014), and noncoding RNA function (Patil et al 2016). Additionally, several studies have uncovered links between m 6 A regulation and disease states: Multiple reports implicate various m 6 A regulatory proteins in cancer (Cui et al 2017, Jaffrey & Kharas 2017, McGuinness & McGuinness 2014, Zhang et al 2017), and several recent studies link m 6 A to viral RNA stability (Gokhale & Horner 2017). Such studies have been critical for our understanding of the broader roles of RNA methylation in physiological processes and human disease.…”

Section: Discussionmentioning

confidence: 99%

Rethinking m⁶A Readers, Writers, and Erasers

Meyer

Jaffrey

2017

Annu. Rev. Cell Dev. Biol.

873

872

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In recent years, m6A has emerged as an abundant and dynamically regulated modification throughout the transcriptome. Recent technological advances have enabled the transcriptome-wide identification of m6A residues, which in turn has provided important insights into the biology and regulation of this pervasive regulatory mark. Also central to our current understanding of m6A are the discovery and characterization of m6A readers, writers, and erasers. Over the last few years, studies into the function of these proteins have led to important discoveries about the regulation and function of m6A. However, during this time our understanding of these proteins has also evolved considerably, sometimes leading to the reversal of early conceptions regarding the reading, writing and erasing of m6A. In this review, we summarize recent advances in m6A research, and we highlight how these new findings have reshaped our understanding of how m6A is regulated in the transcriptome.

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RNA modifications go viral

Cited by 72 publications

References 34 publications

Positive-sense RNA viruses reveal the complexity and dynamics of the cellular and viral epitranscriptomes during infection

Positive-sense RNA viruses reveal the complexity and dynamics of the cellular and viral epitranscriptomes during infection

N⁶-methyladenosine modification and the YTHDF2 reader protein play cell type specific roles in lytic viral gene expression during Kaposi’s sarcoma-associated herpesvirus infection

Rethinking m⁶A Readers, Writers, and Erasers

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RNA modifications go viral

Cited by 72 publications

References 34 publications

Positive-sense RNA viruses reveal the complexity and dynamics of the cellular and viral epitranscriptomes during infection

Positive-sense RNA viruses reveal the complexity and dynamics of the cellular and viral epitranscriptomes during infection

N6-methyladenosine modification and the YTHDF2 reader protein play cell type specific roles in lytic viral gene expression during Kaposi’s sarcoma-associated herpesvirus infection

Rethinking m6A Readers, Writers, and Erasers

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Product

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N⁶-methyladenosine modification and the YTHDF2 reader protein play cell type specific roles in lytic viral gene expression during Kaposi’s sarcoma-associated herpesvirus infection

Rethinking m⁶A Readers, Writers, and Erasers