Anti-viral RNA silencing: do we look like plants?

Abstract

The anti-viral function of RNA silencing was first discovered in plants as a natural manifestation of the artificial 'co-suppression', which refers to the extinction of endogenous gene induced by homologous transgene. Because silencing components are conserved among most, if not all, eukaryotes, the question rapidly arose as to determine whether this process fulfils anti-viral functions in animals, such as insects and mammals. It appears that, whereas the anti-viral process seems to be similarly conserved from plants to insects, even in worms, RNA silencing does influence the replication of mammalian viruses but in a particular mode: micro(mi)RNAs, endogenous small RNAs naturally implicated in translational control, rather than virus-derived small interfering (si)RNAs like in other organisms, are involved. In fact, these recent studies even suggest that RNA silencing may be beneficial for viral replication. Accordingly, several large DNA mammalian viruses have been shown to encode their own miRNAs. Here, we summarize the seminal studies that have implicated RNA silencing in viral infection and compare the different eukaryotic responses.

Figure 1

miRNA biogenesis and action. Long primary transcripts (pri-miRNAs) containing one or several miRNAs are transcribed by RNA polymerase II and cleaved by the Microprocessor Complex, containing at least Drosha (RNAase III endonuclease) and DGCR8/Pasha in human (a double-stranded RNA binding protein). This complex recognizes the double stranded RNA structure of the pri-miRNA and specifically cleaves at the base of the stem loop, hence releasing a 60- to 70-nucleotide precursor(pre)-miRNA. This pre-miRNA is then exported through the Exportin-5 pathway into the cytoplasm where it is further processed into a mature miR/miR* duplex by Dicer, a second RNase III endonuclease. The miR/miR* duplex is then loaded into a multi-component complex, the RNA-induced silencing complex (RISC), constituted of at least TRBP (TAR Binding Protein), Dicer, and one Argonaute (Ago2 in human). The miR serves as a guide for target recognition while the miR* passenger strand is cleaved by Ago2. In contrast to siRNAs (small interfering RNA) and plant miRNAs, which induced the cleavage of the targeted mRNA, most of animal miRNAs harbour an imperfect homology with their targets and, therefore, inhibit translation by a RISC-dependent mechanism that probably interferes with the mRNA cap recognition. This step occurs in cytoplasmic foci called P-bodies (for processing bodies), which contain untranslated mRNAs and can serve as specific sites for mRNA degradation.