Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) expresses ∼20 viral microRNAs (miRNAs) in latently infected cells. We have previously shown that two of these miRNAs function as mimics of the cellular miRNAs miR-155 and miR-142-3p. Two additional KSHV miRNAs, miR-K3+1 and miR-K3, share perfect and offset 5' homology with cellular miR-23, respectively. Here, we report a single nucleotide polymorphism that causes miR-K3+1 expression in a subset of KSHV-infected primary effusion lymphoma cell lines as a consequence of altered processing of the primary transcript by the Microprocessor complex. We confirm that miR-K3+1 regulates miR-23 targets, which is expected because these miRNAs share the entire seed region (nucleotides 2 to 8). Surprisingly, we found that miR-K3 also regulates miR-23 targets, despite offset seed sequences. In addition, the offset homology of miR-K3 to miR-23 likely allows this viral miRNA to expand its target repertoire beyond the targets of miR-23. Because miR-23 is highly expressed in endothelial cells but expressed at only low levels in B cells, we hypothesize that miR-K3 may function to introduce miR-23-like activities into KSHV-infected B cells. Together, our data demonstrate that KSHV has evolved at least three distinct viral miRNAs to tap into evolutionarily conserved cellular miRNA-regulatory networks. Furthermore, our data allow fundamental insights into the generation and functional impact of miRNA 5' end variation.