The degradation of short-lived mRNAs, such as cytokine and protooncogene transcripts, is regulated by proteins that bind to the AU-rich elements (AREs) in the 3′ untranslated region of these mRNAs. Reporting in Cell, Jiahuai Han and colleagues have now discovered a role for microRNAs (miRNAs) in ARE-mediated mRNA decay.

Having established that the decay of ARE-containing mRNA in Drosophila melanogaster S2 cells is regulated in a manner similar to that in mammalian cells, Han and coworkers silenced gene expression in S2 cells using RNA interference to screen for genes required for ARE-mediated mRNA decay. They identified Dicer1, Ago1 and Ago2 — which are all involved in miRNA processing. The requirement for Dicer was confirmed in HeLa cells, as ARERNA was stable in Dicer-defective HeLa cells, but degraded in control cells.

So does the requirement for Dicer and Argonaute (Ago)-family proteins indicate a role for miRNA in ARE-RNA decay? To find out, Han and colleagues analysed human miRNA sequences and identified miR16, which contains eight bases that are complementary to ARE. Indeed, treating HeLa cells with small interfering RNA directed against miR16 — which caused its destruction — increased the stability of ARE-RNA. By contrast, overexpression of miR16 increased the rate of decay. The effect was sequence specific, as a miRNA that does not base pair with ARE had no effect on ARE-mediated mRNA stability.

Tristetraproline (TTP) is an ARE-binding protein that promotes ARE-RNA destabilization. When the authors overexpressed miR16 in TTP-deficient cells, they found that miR16 was unable to destabilize ARE-RNA. Conversely, the destabilizing effect of TTP was not detected when miR16 was absent. So, both miR16 and TTP are required to mediate ARE-RNA decay.

Ultraviolet-crosslinking and immunoprecipitation studies showed that TTP and miR16 are associated, but do not interact directly. TTP also co-precipitated with the predicted human homologue of Ago2. Given that miR16 and Ago proteins are thought to form part of the RNA-induced silencing complex (RISC), this indicates that TTP interacts with miR16 through association with Ago-family members in RISC.

So, although the precise mechanism of miRNA targeting of ARE remains elusive, these data suggest that TTP interacts with RISC to facilitate or stabilize miR16 targeting of ARE, leading to mRNA decay.