1. Department of Molecular Genetics and Microbiology,
2. University Program in Genetics and Genomics,
3. Department of Biostatistics & Bioinformatics, Duke University Medical Center, Durham, North Carolina 27710, USA
4. Cenix BioScience GmbH, Tatzberg 47, 01307 Dresden, Germany
5. Institute for Genome Sciences and Policy,
6. Department of Computer Science, Duke University, Durham, North Carolina 27708, USA
7. Alnylam Pharmaceuticals, Inc., 300 3rd Street, Cambridge, Massachusetts 02142, USA

Correspondence to: Bryan R. Cullen¹ Correspondence and requests for materials should be addressed to B.R.C. (Email: culle002@mc.duke.edu).

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 mRNAs^{3, 4} or downregulate cellular mRNAs^{5, 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 transformation^{8, 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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