The complex world of post-transcriptional mechanisms: is their deregulation a common link for diseases? Focus on ELAV-like RNA-binding proteins

Abstract

Post-transcriptional mechanisms are key determinants in the modulation of the expression of final gene products. Within this context, fundamental players are RNA-binding proteins (RBPs), and among them ELAV-like proteins. RBPs are able to affect every aspect in the processing of transcripts, from alternative splicing, polyadenylation, and nuclear export to cytoplasmic localization, stability, and translation. Of interest, more than one RBP can bind simultaneously the same mRNA; therefore, since each RBP is endowed with different properties, the balance of these interactions dictates the ultimate fate of the transcript, especially in terms of both stability and rate of translation. Besides RBPs, microRNAs are also important contributors to the post-transcriptional control of gene expression. Within this general context, the present review focuses on ELAV-like proteins describing their roles in the nucleus and in the cytoplasm, also highlighting some examples of interactions with other RBPs and with microRNAs. We also examine the putative role and the observed changes of ELAV-like proteins and of their interactions with other regulatory elements in Alzheimer's disease, cancer, and inflammation. The changes in the expression of proteins involved in these diseases are examples of how a derangement in the mRNA stabilization process may be associated with disease development and contribute to pathology. Overall, we hope that the topics handled in the present manuscript provide a hint to look at ELAV-like-mediated mRNA stabilization as a mechanism relevant to disease as well as a novel putative drug target.

Fig. 1

Scheme showing the influence of post-transcriptional mechanisms on mRNA stability/translation. Different signaling cascades are triggered upon distinct stimuli, and their activation influences the interplay among stabilizing, destabilizing RBPs, and miRNAs. The resulting effect has consequences on the target mRNA half-life and/or its translation, thus determining an increase or a decrease of the correspondent protein. Moreover, miRNAs may also interfere with the up-stream signaling cascades [–181] and with the expression of RBPs themselves, as described for ELAVL1 [–109, 150, 163]. A deregulation of this fine balance may play a role in the development of several pathologies, such as Alzheimer’s disease, cancer, and chronic inflammation (see text for more details)

Fig. 2

RBPs interaction in the control of mRNA fate. Stabilizing (SPy) and destabilizing (DPx) RBPs can simultaneously as well as competitively bind to a subset of common transcripts in the nucleus. Subsequently, depending on different factors, either the DPx is released and the SPy remains bound (hence the mRNA is recruited to polysomes and translated) or, vice versa, the SPy is released and the DPx remains bound (hence the mRNA is recruited to the exosome and degraded). Within this context, the best example is proposed by [88] (see text for more details)