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

Abstract

Some viral microRNAs are known to bind host cell mRNAs to block translation or induce their degradation. Now a microRNA from the herpes virus associated with Kaposi's sarcoma has been found to mimic the ubiquitous cellular microRNA, miR-155. The viral version of this RNA, which shows significant homology to the real thing, may have evolved to exploit an existing gene regulatory pathway in host B cells. Viral microRNAs have been shown to downregulate complementary viral mRNA targets and to bind to 3′ untranslated regions of host cell mRNAs to prevent their translation or induce their degradation. This paper shows that viral miRNAs can also function as orthologues of cellular miRNAs and downregulate the expression of cellular mRNAs via target sites that may be evolutionary conserved. 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.