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Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved January 1, 2015 (received for review September 16, 2014)
Significance
As part of the host–pathogen evolutionary arms race, viruses must develop mechanisms to evade host defenses. Viral miRNAs, small regulatory RNAs, are likely key weapons in this struggle. Most previous studies attempted to understand viral miRNA functionality starting with target identification. Here, we use an alternative “functions-first” approach to test the hypothesis that miRNAs from distantly related viruses share common functions. Our work identifies evasion of the antiviral cytokine interferon as a common activity of divergent herpesviral miRNAs. This approach expands our understanding of latent infection and may at least partly explain the resistance of some herpesviral-associated tumors to interferon-mediated therapy. This work demonstrates the utility of functional-based screening for uncovering relevant viral miRNA activities.
Abstract
Diverse viruses encode regulatory RNAs called microRNAs (miRNAs). Despite much progress, the functions of the majority of viral miRNAs remain unknown. Most previous studies have used biochemical methods to uncover targets of viral miRNAs, but it is unclear what fraction of these targets is functionally important. Here, we apply an alternative strategy based on the premise that assorted viral miRNAs will share functionality. Screening a library of >70 human viral miRNAs showed that three unrelated miRNAs from distantly related herpesviruses significantly inhibited IFN signaling. Strikingly, each of these miRNAs directly reduced expression of the cyclic AMP-responsive element-binding protein (CBP), which as part of the p300-CBP complex, mediates IFN signaling. We show that both 5′ and 3′ derivatives from Epstein–Barr virus (EBV) encoded miR-BART-18 precursor miRNA (pre-miRNA) and the orthologous pre-miRNA from Rhesus lymphocryptovirus contribute to reducing IFN signaling. Thus, through both convergent and divergent evolutionary mechanisms, varied herpesviral miRNAs share the ability to decrease IFN signaling. Restoring miR-BART-18 to cells infected with an EBV miRNA mutant conveyed a cellular growth advantage upon IFN treatment, and relevant miRNAs from other herpesviruses were able to complement this activity. Blocking miR-BART-18 function in an EBV+ tumor cell line renders cells more susceptible to IFN-mediated effects. These findings provide a mechanism that can at least partially explain the resistance of some EBV-associated tumors to IFN therapy. Our work suggests that similar pan-viral-miRNA functional-based screening strategies are warranted for determining relevant activities of other viral miRNAs.
Footnotes
- ↵1To whom correspondence should be addressed. Email: Chris_sullivan{at}austin.utexas.edu.
Author contributions: J.E.C., A.G., and C.S.S. designed research; J.E.C. performed research; L.V.M. contributed new reagents/analytic tools; J.E.C. and C.S.S. analyzed data; and J.E.C. and C.S.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1417891112/-/DCSupplemental.
- aDepartment of Molecular Biosciences, Center for Systems and Synthetic Biology, Center for Infectious Disease, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712-0162; and
- bDepartment of Cell & Tissue Biology, University of California, San Francisco, CA 94143-0512
Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved January 1, 2015 (received for review September 16, 2014)
Significance
As part of the host–pathogen evolutionary arms race, viruses must develop mechanisms to evade host defenses. Viral miRNAs, small regulatory RNAs, are likely key weapons in this struggle. Most previous studies attempted to understand viral miRNA functionality starting with target identification. Here, we use an alternative “functions-first” approach to test the hypothesis that miRNAs from distantly related viruses share common functions. Our work identifies evasion of the antiviral cytokine interferon as a common activity of divergent herpesviral miRNAs. This approach expands our understanding of latent infection and may at least partly explain the resistance of some herpesviral-associated tumors to interferon-mediated therapy. This work demonstrates the utility of functional-based screening for uncovering relevant viral miRNA activities.
Abstract
Diverse viruses encode regulatory RNAs called microRNAs (miRNAs). Despite much progress, the functions of the majority of viral miRNAs remain unknown. Most previous studies have used biochemical methods to uncover targets of viral miRNAs, but it is unclear what fraction of these targets is functionally important. Here, we apply an alternative strategy based on the premise that assorted viral miRNAs will share functionality. Screening a library of >70 human viral miRNAs showed that three unrelated miRNAs from distantly related herpesviruses significantly inhibited IFN signaling. Strikingly, each of these miRNAs directly reduced expression of the cyclic AMP-responsive element-binding protein (CBP), which as part of the p300-CBP complex, mediates IFN signaling. We show that both 5′ and 3′ derivatives from Epstein–Barr virus (EBV) encoded miR-BART-18 precursor miRNA (pre-miRNA) and the orthologous pre-miRNA from Rhesus lymphocryptovirus contribute to reducing IFN signaling. Thus, through both convergent and divergent evolutionary mechanisms, varied herpesviral miRNAs share the ability to decrease IFN signaling. Restoring miR-BART-18 to cells infected with an EBV miRNA mutant conveyed a cellular growth advantage upon IFN treatment, and relevant miRNAs from other herpesviruses were able to complement this activity. Blocking miR-BART-18 function in an EBV+ tumor cell line renders cells more susceptible to IFN-mediated effects. These findings provide a mechanism that can at least partially explain the resistance of some EBV-associated tumors to IFN therapy. Our work suggests that similar pan-viral-miRNA functional-based screening strategies are warranted for determining relevant activities of other viral miRNAs.
- p300/CBP
- latency
- KSHV
- HCMV
- RNAi
Footnotes
- ↵1To whom correspondence should be addressed. Email: Chris_sullivan{at}austin.utexas.edu.
Author contributions: J.E.C., A.G., and C.S.S. designed research; J.E.C. performed research; L.V.M. contributed new reagents/analytic tools; J.E.C. and C.S.S. analyzed data; and J.E.C. and C.S.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1417891112/-/DCSupplemental.
Diverse viral miRNAs inhibit interferon signaling
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