Selective Degradation of Host MicroRNAs by an Intergenic HCMV Noncoding RNA Accelerates Virus Production

• A HCMV clinical strain selectively degrades miRNAs within the host miR-17-92 cluster
• A HCMV intergenic noncoding RNA in UL144-145 region, miRDE, mediates host miRNA turnover
• miRDE directs miRNA turnover via sequence-specific noncanonical miRNA-mRNA interactions
• miRDE is specific to virus clinical strain, and its action accelerates HCMV lytic growth

SummaryVirulence of human cytomegalovirus (HCMV) clinical isolates correlates with carriage of a 15 kb segment in the UL/b′ region of the viral genome, which is absent from attenuated strains. The mechanisms by which this segment contributes to HCMV virulence remain obscure. We observed that intergenic RNA sequences within the 15 kb segment function as a microRNA (miRNA) decay element (miRDE) and direct the selective, sequence-specific turnover of mature miR-17 and miR-20a encoded within the host miR-17-92 cluster. Unlike canonical miRNA-mRNA interactions, the miRNA-miRDE interactions did not repress miRDE expression. miRNA binding site mutations retargeted miRDE to other miR-17-92 cluster miRNAs, which are otherwise resistant to miRDE-mediated decay. miRDE function was required to accelerate virus production in the context of lytic HCMV infection. These results indicate a role for viral noncoding RNA in regulating cellular miRNAs during HCMV pathogenesis and suggest that noncoding RNAs may play a role in mature miRNA turnover.

Graphical AbstractFigure optionsDownload high-quality image (235 K)Download as PowerPoint slide