How Do Viruses Avoid Inhibition by Endogenous Cellular MicroRNAs?

MicroRNAs (miRNAs) are an extensive family of small regulatory RNAs that function by binding to complementary mRNAs, primarily in the 3′ untranslated region (3′UTRs), and then inhibiting their expression by reducing mRNA translation and/or stability [1]. MiRNAs are initially transcribed as long pri-miRNAs, which are sequentially processed by the RNase III enzymes Drosha, in the nucleus, and Dicer, in the cytoplasm, to generate the mature, ∼22-nt miRNA [2]. This is then loaded into the RNA Induced Silencing Complex (RISC), which consists minimally of one of the four mammalian Argonaut proteins, Ago1 to Ago4, as well as a member of the GW182 protein family. MiRNAs function as guide RNAs to target RISC to complementary mRNA sequences on specific mRNA 3′UTRs. Analysis has revealed that complementarity to nucleotides 2 through 8 of the miRNA, the so-called seed region, is particularly important for effective RISC recruitment [1], although non-canonical sites, with incomplete seed complementarity, have also been reported [3]. Importantly, RISC recruitment to target sites that are occluded by RNA secondary structure or bound proteins is very inefficient [4].