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Abstract
Cytomegaloviruses express large amounts of viral miRNAs during lytic infection, yet, they only modestly alter the cellular miRNA profile. The most prominent alteration upon lytic murine cytomegalovirus (MCMV) infection is the rapid degradation of the cellular miR-27a and miR-27b. Here, we report that this regulation is mediated by the ∼1.7 kb spliced and highly abundant MCMV m169 transcript. Specificity to miR-27a/b is mediated by a single, apparently optimized, miRNA binding site located in its 3′-UTR. This site is easily and efficiently retargeted to other cellular and viral miRNAs by target site replacement. Expression of the 3′-UTR of m169 by an adenoviral vector was sufficient to mediate its function, indicating that no other viral factors are essential in this process. Degradation of miR-27a/b was found to be accompanied by 3′-tailing and -trimming. Despite its dramatic effect on miRNA stability, we found this interaction to be mutual, indicating potential regulation of m169 by miR-27a/b. Most interestingly, three mutant viruses no longer able to target miR-27a/b, either due to miRNA target site disruption or target site replacement, showed significant attenuation in multiple organs as early as 4 days post infection, indicating that degradation of miR-27a/b is important for efficient MCMV replication in vivo.
Highlights
MicroRNAs are small non-coding RNA molecules, which are involved in a broad range of biological processes
We reported on the rapid degradation of two cellular miRNAs upon lytic murine cytomegalovirus (MCMV) infection, namely miR-27a and miR-27b
Three mutant viruses unable to target miR-27a/b showed significantly lower virus titers in various organs during acute MCMV infection, indicating that degradation of miR-27a/b is important for efficient virus replication in vivo
Summary
MicroRNAs (miRNAs) are small non-coding RNA molecules, which are involved in a broad range of biological processes. They represent an evolutionary highly conserved mechanism present in virtually all multicellular organisms ranging from fungi to mammals (reviewed in [1]). MiRNA biogenesis is a stepwise process involving the sequential action of the RNase III enzymes Drosha and Dicer, generating a ,22 nucleotide (nt) miRNA duplex. One strand of the duplex is loaded into the RNAinduced silencing complex (RISC), while the other strand, known as the passenger strand or star sequence (miRNA*), is often, but not always, actively degraded. Once incorporated into RISC, the loaded miRNA is thought to be rather stable, with a half-life in the range of days [3]
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