RNA-mediated degradation of microRNAs: A widespread viral strategy?

Abstract

Regulation of small RNAs by other non-coding RNAs is a ubiquitous feature of gene regulatory systems that can be exploited by viruses. Examples of this have been described in 3 different herpesviruses, where viral non-coding RNAs bind to highly abundant cellular (miRNAs), mediating their degradation: miR-27 is targeted by both murine cytomegalovirus and herpesvirus saimiri, while the miR-17 family is targeted by human cytomegalovirus. We review what is known about RNA-mediated regulation of miRNA stability and propose 3 potential roles that viral non-coding RNAs might assume to initiate the destruction of a miRNA, acting as "recruiters," "localizers" or "exposers." Whereas the miRNAs (miR-17 and miR-27) appear to be ancient and pre-date the common ancestor of all mammalian herpesviruses, comparative analyses of herpesvirus genomes indicate that the 3 known viral regulators of miRNA each evolved independently, and much more recently. Noting that the anti-viral activity of miRNAs might be countered by a variety of mechanisms, we propose that (i) there has been continual turnover of these mechanisms during herpesvirus evolution, and (ii) there may be many other, as yet undescribed, anti-miRNA activities encoded by other herpesviruses and indeed by viruses from other families.

Keywords: IL-10; RNA degradation; RNAi; herpesvirus; miRNA response element; microRNA; microRNA turnover; viral evolution.

Figure 1.

Phylogenetic relationships among representative mammalian herpesviruses, showing the branches on which 3 distinct miRNA regulators appear to have evolved (circles), and 4 occasions where IL10 genes have been acquired (triangles). Ancestral branches leading to the α, β and gamma subfamilies of herpesviruses are indicated. Virus acronyms are explained, and sequence sources are given, in Supplementary Table 1.

Figure 2.

miRNA binding sites in herpesviruses. Sites within viral RNAs that are complementary to miRNAs are shown in red; black lines (or dots for G-U) show sites where potential binding is conserved. Conserved sequences in the miR-17 family members are denoted with a black line. Virus acronyms are explained, and sequence sources are given, in Supplementary Table 1.