MicroRNAs (miRNAs) are ~22-nt regulatory RNAs expressed by all multicellular eukaryotes. Humans encode >700 miRNAs and similar numbers are likely to exist in other mammalian species. Almost all cellular miRNAs are initially transcribed by RNA polymerase II (Pol II) as part of a long, capped, polyadenylated primary miRNA (pri-miRNA) precursor. The miRNA forms part of one arm of an RNA stem-loop that consists of an ~32-bp imperfect stem flanked by unstructured RNA sequences. This stem-loop is recognized by the nuclear RNase III enzyme Drosha, which cleaves the stem to liberate an ~60-nt pre-miRNA hairpin. The pre-miRNA is then transported to the cytoplasm where it is cleaved by a second RNase III enzyme, called Dicer, which removes the terminal loop to generate the miRNA duplex intermediate. One strand of this duplex is incorporated into the RNA-induced silencing complex (RISC), where it acts as a guide RNA to direct RISC to complementary mRNA species. Depending on the level of complementarity, RISC can either cleave bound mRNAs and/or inhibit their translation. Inhibition of mRNA translation generally requires full complementarity of the mRNA to nucleotides 2 through 7 or 8 from the miRNA 5′ end – the miRNA seed region. The primary, and possibly sole, function of mammalian miRNAs is therefore to act as specific post-transcriptional inhibitors of mRNA function.
- Do All Viruses Encode miRNAs? In general, we can divide mammalian viruses into three categories, i.e., the herpesviruses, which encode multiple viral miRNAs; other nuclear DNA viruses, which may encode one or two miRNAs; and the RNA viruses and cytoplasmic DNA viruses, which appear to lack any miRNAs.
- What Do Viral miRNAs Do? Virus miRNAs may serve two major functions. First, to inhibit the expression of cellular factors that play a role in cellular innate or adaptive antiviral immune responses. Second, to downregulate the expression of virus regulatory proteins.
- Are Virus miRNAs Conserved between Related Virus Species? No, but the miRNAs of individual viruses are conserved.
- Do Viruses Regulate miRNA Transcription, Processing, or Function? At present, there is no evidence indicating that viruses modify the cellular environment to selectively favor the processing and expression of viral miRNAs, although viral miRNAs may be expressed at such high levels that they have the potential to competitively inhibit cellular miRNA function.
- Can Viruses Use Cellular miRNAs to Promote Their Replication? At least one clear-cut example of a cellular miRNA that facilitates virus replication is known, activation of HCV replication by the liver-specific miRNA miR-122.