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A viral microRNA functions as an orthologue of cellular miR-155

Abstract

All metazoan eukaryotes express microRNAs (miRNAs), roughly 22-nucleotide regulatory RNAs that can repress the expression of messenger RNAs bearing complementary sequences1. Several DNA viruses also express miRNAs in infected cells, suggesting a role in viral replication and pathogenesis2. Although specific viral miRNAs have been shown to autoregulate viral mRNAs3,4 or downregulate cellular mRNAs5,6, the function of most viral miRNAs remains unknown. Here we report that the miR-K12-11 miRNA encoded by Kaposi’s-sarcoma-associated herpes virus (KSHV) shows significant homology to cellular miR-155, including the entire miRNA ‘seed’ region7. Using a range of assays, we show that expression of physiological levels of miR-K12-11 or miR-155 results in the downregulation of an extensive set of common mRNA targets, including genes with known roles in cell growth regulation. Our findings indicate that viral miR-K12-11 functions as an orthologue of cellular miR-155 and probably evolved to exploit a pre-existing gene regulatory pathway in B cells. Moreover, the known aetiological role of miR-155 in B-cell transformation8,9,10 suggests that miR-K12-11 may contribute to the induction of KSHV-positive B-cell tumours in infected patients.

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Figure 1: Expression of miR-K12-11 and miR-155 in BJAB cells.
Figure 2: miR-K12-11 and miR-155 regulate a common set of mRNAs.
Figure 3: Direct and equivalent regulation of candidate 3′ UTRs by miR-K12-11 and miR-155.
Figure 4: Endogenous BACH1 and Fos proteins are repressed by both miR-K12-11 and miR-155.

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Acknowledgements

We thank T. Curran for rabbit anti-Fos antiserum. Flow cytometry was performed by J. Whitesides in the Duke Center for AIDS Research BSL3 Flow Cytometry Core Facility. Microarrays were performed in the Duke Microarray Facility. This research was supported by a National Institutes of Health grant to B.R.C. and by a Feodor Lynen Fellowship to E.G. U.O. is an Alfred P. Sloan Fellow in Computational Molecular Biology.

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Correspondence to Bryan R. Cullen.

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Competing interests

J. Soutschek, R. Braich and M. Manoharan are employees of Alnylam Pharmaceuticals, Inc., which develops therapeutics based on siRNAs. C. Sachse and C. Frenzel are employees of Cenix BioScience GmbH, which is a specialist in RNAi-based discovery and functional characterization of therapeutic targets and drug candidates. The remaining authors declare no competing interests.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-7 and Legends, Supplementary Tables 1-3 and Legends and Supplementary Tables 4-5 of primers. The Supplementary Figures show control data and additional experimental data in support of the manuscript’s conclusions. (PDF 2298 kb)

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Gottwein, E., Mukherjee, N., Sachse, C. et al. A viral microRNA functions as an orthologue of cellular miR-155. Nature 450, 1096–1099 (2007). https://doi.org/10.1038/nature05992

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