Functional interplay between RNA-binding protein HuR and microRNAs

Abstract

The mammalian RNA-binding protein (RBP) HuR associates with numerous mRNAs encoding proteins with roles in cell division, cell survival, immune response, and differentiation. HuR was known to stabilize many of these mRNAs and/or modulated their translation, but the molecular processes by which HuR affected the fate of target mRNAs was largely unknown. Evidence accumulated over the past five years has revealed that the influence of HuR on many bound transcripts depends on HuR's interplay with microRNAs which associate with the same mRNAs. Here, we review the interactions of HuR and microRNAs - both competitive and cooperative - that govern expression of shared target mRNAs. Competition between HuR and microRNAs typically results in enhanced gene expression if the HuR-mRNA interaction prevails, and in repression if the microRNA remains associated. Cooperation between HuR and microRNAs leads to lower expression of the shared mRNA. We also describe the regulation of HuR levels by microRNAs as well as the regulation of microRNA levels by HuR. Finally, we discuss transcriptome-wide analyses of HuR-bound mRNAs with neighboring microRNA sites, and review the emerging mechanisms whereby microRNAs confer versatility and robustness to the post-transcriptional outcomes of HuR targets.

Fig. 1. Schematic of competitive and cooperative interactions of HuR and microRNAs on shared target mRNAs

Top, under the ‘competition’ model, binding of miRNA-RISC may trigger a conformational change that hides the site of HuR binding to the mRNA, in turn lowering expression of the mRNA (left); conversely, HuR binding may trigger changes in RNA structure that conceal the site of interaction with miRNA-RISC, causing increased expression of the mRNA (right). Bottom, in the ‘cooperation’ model, binding of HuR may trigger conformational changes that allow binding of miRNA-RISC or vice versa, resulting in repression of the mRNA.