Mechanisms coordinating ELAV/Hu mRNA regulons

Abstract

The 5' and 3' untranslated regions (UTRs) of messenger RNAs (mRNAs) function as platforms that can determine the fate of each mRNA individually and in aggregate. Multiple mRNAs that encode proteins that are functionally related often interact with RNA-binding proteins (RBPs) and noncoding RNAs (ncRNAs) that coordinate their expression in time and space as RNA regulons within the ribonucleoprotein (RNP) infrastructure we term the ribonome. Recent ribonomic methods have emerged that can determine which mRNAs are bound and regulated by RBPs and ncRNAs, some of which act in combination to determine global outcomes. ELAV/Hu proteins bind to AU-rich elements (ARE) in mRNAs and regulate their stability from splicing to translation, and the ubiquitous HuR protein has been implicated in cancerous cell growth. Recent work is focused on mechanistic models of how ELAV/Hu proteins increase mRNA stability and translation by repressing microRNAs (miRs) and the RNA induced silencing complex (RISC) via ARE-based ribonucleosomes that may affect global functions of mRNA regulons.

Figure 1. Depiction of the cytoplasmic mobilization of HuR known to occur during various activation conditions as well as the proliferative states of transformed cells [21, 26]

In quiescent and non-transformed cells, HuR protein (red circles) is primarily nuclear, and ARE-containing mRNAs are rapidly destabilized by the RISC-miR complex or other destabilizing RBPs [21]. In highly proliferating cells (including cancer cells), as well as in response to certain environmental stresses, HuR protein is shuttled to the cytoplasm where it can stabilize normally labile mRNA targets, potentially through antagonizing destabilizing factors [21,69,71-73,77,78]. The boxes at the bottom show established mRNA targets of HuR and many miRs [26]. HuR and miRs regulate overlapping subsets of mRNAs encoding proteins involved in the acquisition of cancer-related phenotypes [27].

Figure 2. Ribonucleosome model depicting antagonism of the miR/RISC mRNA destabilizing complex by proximal binding of HuR and possibly other members of the ELAV/Hu RBP family [27,82]

In the example, a single molecule of HuR binds at a U-rich RNA-recognition element followed by cooperative binding of multiple HuR molecules [15,19-21,31-37]. Depending on the exact spacing between the nucleation site and the miR/RISC, multimeric binding of HuR could result in steric hindrance or physical displacement of the RISC. This event would logically antagonize the destabilization functions of miR/RISC [29] resulting in increased stability of the mRNA target by HuR, and plausibly, all ELAV/Hu RBPs as demonstrated [16-17,21-23]. The model suggests that a HuR ribonucleosome may displace the miRNP to stabilize mRNA targets. However, the precise binding motifs and coding rules that determine nucleation and multimerization of HuR are poorly understood and may differ with each message [15,31,34,35].