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.

Keywords: RNA-binding proteins; autoregulation; competition; cooperation; post-transcriptional regulation; regulatory elements; regulatory networks.

Figure 1

RBPs regulatory interplay modes. The figure shows the different patterns of regulatory interaction observed between RNA-binding proteins. We use a hypothetical mRNA 3′UTR as the interaction substrate to illustrate these mechanisms. (A) Describes the cooperative interplay mode. We have proximal cooperative binding (up) when two RBPs physically interact through nearby binding sites (or distant sites brought in proximity by the RNA secondary structure conformation), thus shaping their action through this interaction. RBPs can also cooperate through distant binding sites and without interacting directly (down), exerting their synergistic activity independently from one another. (B) Represents the competitive interplay mode. This pattern consists of two RBPs (RBP1 and RBP2), contending for binding to one or more overlapping binding sites on an RNA species. This competition results in a balance of RBP1 and RBP2 bound to these molecules, which determines the outcome of the regulation. (C) Describes the mutual interplay mode. Here, two RBPs (RBP1 and RBP2) can control the expression of one another to constrain and fine-tune the outcome of the regulation of their target RNAs. This mechanism can be heterogeneous (up), with RBP2 binding to RBP1 mRNA (or vice-versa) or autogenous (down), where an RBP binds to its cognate mRNA.

Figure 2

Examples of RBP interplay mechanisms. The figure illustrates an occurrence of each RBP interaction mode. (A) Shows the 5′UTR-mediated cooperation of DDX3X and CAPRIN1 which controls the translation of RAC1 mRNA. This RNA-dependent association exploits a further interaction with PABPC1 at the leading edge of the cell to promote fibroblasts migration and spreading (Copsey et al., 2017). (B) Depicts the antagonistic interaction of YBX1 and PABPC1 on the 3′UTR of YBX1 mRNA. This two RBPs target overlapping binding sites within the same regulatory element (the YBX1 binding sequence is shown). While PABPC1 stimulates YBX1 mRNA translation in a poly(A)-tail-independent manner, YBX1 attempts to repress it by inhibiting translation initiation (Lyabin et al., 2011). (C) Portrays the mutual heterogeneous interaction between the ELAVL1 and MSI1 RBPs. ELAVL1 binds to an AU-rich element in the distal part of the 3′UTR of MSI1 mRNA (the ELAVL1 binding sequence is shown). This binding induces higher steady-state levels of MSI1 mRNA by exerting a stabilizing effect. In turn, this enhances MSI1 translation, ultimately leading to upregulation of its protein levels (Vo et al., 2012).