MicroRNAs (miRNAs) negatively regulate gene expression and it is estimated that at least 30% of all protein encoding genes are controlled by miRNAs at the post-transcriptional level. While it is clear that miRNAs both inhibit translation and decrease mRNA stability whether these pathways act in parallel or occur in an ordered sequence of events remains unknown. Using well characterised viral IRESs we show that miRNAs require translational repression and in its absence, gene silencing does not occur. Importantly we show that these mRNAs that cannot be inhibited by miRNAs are still associated with the miRNA and the Ago complex but in the absence of translational inhibition mRNA destabilisation does not occur. Together these data strongly suggest a linear pathway by which miRNAs inhibit translation as the priming event.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.