Viruses and microRNAs: RISCy interactions with serious consequences

Abstract

Analyses of small RNA expression profiles have revealed that several DNA viruses-including particularly, herpesviruses-express high levels of multiple viral microRNAs (miRNAs) in infected cells. Here, I review our current understanding of how viral miRNAs influence viral replication and pathogenesis and discuss how viruses reshape the pattern of cellular miRNA expression. Indeed, viruses are now known to both activate and repress the expression of specific cellular miRNAs, and disrupting this process can perturb the ability of viruses to replicate normally. In addition, it is now clear that virally encoded miRNAs play a key role in inhibiting antiviral innate immune responses and can also promote cell transformation in culture. While our understanding of how viruses interact with miRNAs remains somewhat rudimentary, it is nevertheless already clear that these interactions can play a critical role in mediating viral pathogenesis and therefore may represent novel and highly specific targets for therapeutic intervention.

Figure 1.

Schematic representation of the known miRNA biogenesis pathways in mammalian cells. (A) In the canonical miRNA processing pathway, Drosha liberates the pre-miRNA by direct cleavage of the pri-miRNA. (B) In the miRtron pathway, the pre-miRNA is generated by pre-mRNA splicing. (C) The miRNA expression pathway used by MHV68 requires processing of a tRNA:pre-miRNA fusion intermediate by tRNAseZ to liberate the pre-miRNA. (D) In this final pathway, short structured RNAs, generated by Pol III transcription, are directly exported to the cytoplasm, where they are cleaved by Dicer. As shown, export is mediated by Exp5, but this may not always be the case.

Figure 2.

Schematic of the miRNA locus in KSHV. (A) This figure shows a simplified schematic of the latency region of KSHV at the genomic level, including the four major latency-specific gene products and the 12 KSHV pre-miRNAs. (B) The two major latency-specific promoters (green arrows) give rise to a complex mixture of mRNAs, depending on alternative splicing and polyadenylation, that express all four latent proteins and all 12 viral pre-miRNAs. (C) Upon activation of lytic replication, a powerful lytic promoter (red arrow) is activated that transcribes RNAs encoding the KapB protein and two of the 12 viral miRNAs. As discussed in the text, lytic replication also results in inhibition of Drosha expression, which favors KapB mRNA production over miRNA biogenesis.