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The human cytomegalovirus microRNA miR-UL112 acts synergistically with a cellular microRNA to escape immune elimination

Nature Immunology volume 11, pages 806–813 (2010)Cite this article

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Abstract

Although approximately 200 viral microRNAs are known, only very few share similar targets with their host's microRNAs. A notable example of this is the stress-induced ligand MICB, which is targeted by several distinct viral and cellular microRNAs. Through the investigation of the microRNA-mediated immune-evasion strategies of herpesviruses, we initially identified two new cellular microRNAs that targeted MICB and were expressed differently both in healthy tissues and during melanocyte transformation. We show that coexpression of various pairs of cellular microRNAs interfered with the downregulation of MICB, whereas the viral microRNAs optimized their targeting ability to efficiently downregulate MICB. Moreover, we demonstrate that through site proximity and possibly inhibition of translation, a human cytomegalovirus (HCMV) microRNA acts synergistically with a cellular microRNA to suppress MICB expression during HCMV infection.

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Figure 1: Newly identified cellular microRNAs that downregulate MICB.
Figure 2: The microRNAs miR-376a and miR-433 directly bind the 3′ UTR of MICB, repress its translation and reduce NK cell cytotoxicity.
Figure 3: Expression patterns of MICB-targeting microRNAs in various cell lines and in healthy human tissues.
Figure 4: MICB expression is upregulated in cell lines expressing anti-microRNA sponges, which results in increased killing by NK cells.
Figure 5: Coexpression of cellular microRNAs antagonizes the repression of MICB expression.
Figure 6: The microRNAs miR-UL112 and miR-376a act synergistically to downregulate MICB expression.
Figure 7: Synergistic control of MICB expression by miR-376a and miR-UL112 during HCMV infection.

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Acknowledgements

We thank A. Bernard (Hôpital de l'Archet, Nice, France) for monoclonal anti-CD99 (12E7); Y. Livneh, D. Davis and S. Jonjic and all members of the Mandelboim laboratory for suggestions and discussions and for critical reading of the manuscript; S. Diederichs and W. Filipowicz for discussions and suggestions; and M. Lotem and team (Hadassah Hospital) for primary melanocytes and nevi. Supported by the Israeli Science Foundation (O.M.), The Israeli Science Foundation (Morasha, to O.M.), Croatia-Israel Research (O.M.), Ministry of Science and Technology–Deutsches Krebsforschungszentrum (O.M.), The European Consortium (MRTN-CT-2005 to O.M.), Rosetrees Trust (O.M.), the Israel Cancer Association (20100003 to O.M.) and the Association for International Cancer Research (O.M.).

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Authors and Affiliations

  1. The Lautenberg Center for General and Tumor Immunology, The BioMedical Research Institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem, Israel

    Daphna Nachmani, Dikla Lankry & Ofer Mandelboim

  2. Virology Unite, Hadassah Hospital, The Hebrew University Hadassah Medical School, Jerusalem, Israel

    Dana G Wolf

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  1. Daphna Nachmani
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D.N. did all experiments, analyzed the data and wrote the paper; D.L. and D.G.W. provided reagents; and O.M. supervised the project.

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Correspondence to Ofer Mandelboim.

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Nachmani, D., Lankry, D., Wolf, D. et al. The human cytomegalovirus microRNA miR-UL112 acts synergistically with a cellular microRNA to escape immune elimination. Nat Immunol 11, 806–813 (2010). https://doi.org/10.1038/ni.1916

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