Handshakes and Fights: The Regulatory Interplay of RNA-Binding Proteins

Abstract

What drives the flow of signals controlling the outcome of post-transcriptional regulation of gene expression? This regulatory layer, presiding to processes ranging from splicing to mRNA stability and localization, is a key determinant of protein levels and thus cell phenotypes. RNA-binding proteins (RBPs) form a remarkable army of post-transcriptional regulators, strong of more than 1,500 genes implementing this expression fine-tuning plan and implicated in both cell physiology and pathology. RBPs can bind and control a wide array of RNA targets. This sheer amount of interactions form complex regulatory networks (PTRNs) where the action of individual RBPs cannot be easily untangled from each other. While past studies have mostly focused on the action of individual RBPs on their targets, we are now observing an increasing amount of evidence describing the occurrence of interactions between RBPs, defining how common target RNAs are regulated. This suggests that the flow of signals in PTRNs is driven by the intertwined contribution of multiple RBPs, concurrently acting on each of their targets. Understanding how RBPs cooperate and compete is thus of paramount importance to chart the wiring of PTRNs and their impact on cell phenotypes. Here we review the current knowledge about patterns of RBP interaction and attempt at describing their general principles. We also discuss future directions which should be taken to reach a comprehensive understanding of this fundamental aspect of gene expression regulation.

p53-induced apoptosis is specified by a translation program regulated by PCBP2 and DHX30

“…It is likely that other proteins are involved along with PCBP2 and DHX30 in the interaction with target RNAs at CGPD-motif sites, as suggested also by the mass-spectrometry data. As observed for other families of RBPs, the eventual mRNA fate can depend on the results of the interplay between different RBPs or RBP complexes targeting the same specific cis-element (Dassi, 2017;Lal et al, 2004). This hypothesis is supported by the fact that DHX30 depletion led to a significant increase in Nutlin-dependent apoptosis 48 hours after treatment, while PCBP2 silenced cells did not exhibit more Nutlin-dependent apoptosis (Figure 5E, 5F).…”

5’ UTR variants in the quantitative trait geneHnrnph1support reduced 5’ UTR usage and hnRNP H protein as a molecular mechanism underlying reduced methamphetamine sensitivity

“…Together, these results indicate that D2J variants within and surrounding the 5' UTR of Hnrnph1 leads to exclusion of exon 3, which in turn leads to a functional decrease in protein translation. These variants may also cause other functional changes in the 5' UTR leading to a decrease in protein translation by modifying the regulatory elements within the promoter to reduce efficacy of translation (40), or changing the binding sites for other RNA-binding proteins (RBPs) to repress initiation of translation (41,42).…”

Differential RNA editing between epithelial and mesenchymal tumors impacts mRNA abundance in immune response pathways

“…Since mRNA stability is closely regulated by RNA-binding proteins (RBPs) [49][50][51][52] , we next asked whether RBPs are involved in the modulation of mRNA abundance by RNA editing sites. To this end, we analyzed enhanced ultraviolet crosslinking and immunoprecipitation (eCLIP) datasets of 126 RBPs in two cell lines (HepG2 and K562) from ENCODE 46,53 .…”