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miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator

Nature Cell Biology volume 12, pages 513–519 (2010)Cite this article

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Abstract

MicroRNAs are small, non-coding RNAs that negatively regulate gene expression1. It has been proposed that microRNAs could function in the regulation of innate immunity2,3, but this has not been demonstrated for viral infection. Here we test this hypothesis using the human pathogenic virus Kaposi's sarcoma-associated herpesvirus (KSHV) and one of its putative natural cellular targets, primary lymphatic endothelial cells4 (LECs). We show that an early antiviral microRNA response (6 h post-infection) includes expression of microRNAs that enhance viral gene expression. In particular, the CREB-induced miR-132 microRNA is highly upregulated after infection and has a negative effect on the expression of interferon-stimulated genes, facilitating viral replication. We show a similar function for miR-132 during infection of monocytes with herpes simplex virus-1 (HSV-1) and human cytomegalovirus (HCMV). miR-132 regulates innate antiviral immunity by inhibiting expression of the p300 transcriptional co-activator. p300 is downregulated early after KSHV infection, and inhibition of miR-132 induction restores p300 expression. Furthermore, p300 regulates miR-132 levels, revealing a dynamic equilibrium between miR-132 and p300. By targeting p300, rather than a transcription factor or signalling protein, miR-132 has a broad role in the regulation of antiviral immunity.

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Figure 1: MicroRNAs induced early after KSHV infection enhance viral gene expression.
Figure 2: miR-132 is induced through a CREB-dependent mechanism.
Figure 3: miR-132 inhibits the antiviral interferon response and enhances viral replication.
Figure 4: p300 is a target of miR-132.
Figure 5: miR-132 regulates viral gene expression through suppression of p300.

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Acknowledgements

This work was funded by the U.K. Medical Research Council and Cancer Research U.K. We thank G. Wilkinson and R. Stanton for providing HCMV and C. Atkinson for help with HCMV qPCR. We are grateful to members of the Cancer Research UK Viral Oncology Group, in particular J. Funes and V. Emuss for advice and discussions.

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Authors and Affiliations

  1. Cancer Research UK Viral Oncology Group, UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, University College London, WC1E 6BT, London

    Dimitrios Lagos, Gabriel Pollara, Stephen Henderson, Fiona Gratrix & Chris Boshoff

  2. MRC Laboratory of Molecular Biology, Hills Road, CB2 0QH, Cambridge

    Martin Fabani

  3. UCL Centre for Virology, Royal Free Hospital, Rowland Hill Street, University College London, NW3 2PF, London

    Richard S.B. Milne

  4. Department of Immunology, Chelsea and Westminster Hospital, 369 Fulham Road, Imperial College, SW10 9NH, London, U.K.

    Frances Gotch

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  1. Dimitrios Lagos
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Contributions

D.L. and C.B. designed experiments and wrote the paper. D.L., G.P. and M.F. performed experiments. S.H. performed bioinformatic analyses. F.Gr. constructed reagents. R.M. provided HCMV and HSV-1 and contributed to experimental design. F.Go. contributed to experimental design.

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Correspondence to Dimitrios Lagos or Chris Boshoff.

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Lagos, D., Pollara, G., Henderson, S. et al. miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator. Nat Cell Biol 12, 513–519 (2010). https://doi.org/10.1038/ncb2054

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