Post-translational Control of RNA-Binding Proteins and Disease-Related Dysregulation

Abstract

Cell signaling mechanisms modulate gene expression in response to internal and external stimuli. Cellular adaptation requires a precise and coordinated regulation of the transcription and translation processes. The post-transcriptional control of mRNA metabolism is mediated by the so-called RNA-binding proteins (RBPs), which assemble with specific transcripts forming messenger ribonucleoprotein particles of highly dynamic composition. RBPs constitute a class of trans-acting regulatory proteins with affinity for certain consensus elements present in mRNA molecules. However, these regulators are subjected to post-translational modifications (PTMs) that constantly adjust their activity to maintain cell homeostasis. PTMs can dramatically change the subcellular localization, the binding affinity for RNA and protein partners, and the turnover rate of RBPs. Moreover, the ability of many RBPs to undergo phase transition and/or their recruitment to previously formed membrane-less organelles, such as stress granules, is also regulated by specific PTMs. Interestingly, the dysregulation of PTMs in RBPs has been associated with the pathophysiology of many different diseases. Abnormal PTM patterns can lead to the distortion of the physiological role of RBPs due to mislocalization, loss or gain of function, and/or accelerated or disrupted degradation. This Mini Review offers a broad overview of the post-translational regulation of selected RBPs and the involvement of their dysregulation in neurodegenerative disorders, cancer and other pathologies.

Phosphorylation of mRNA-Binding Proteins Puf1 and Puf2 by TORC2-Activated Protein Kinase Ypk1 Alleviates Their Repressive Effects

“…The most important conclusion of the work presented here is that phosphorylation of Puf1 and Puf2 by the protein kinase Ypk1 is yet another mechanism by which the TORC2-Ypk1 signaling axis controls the composition and function of the PM. In this sense, the regulatory circuitry we have described here joins a growing list of examples which illustrate that phosphorylation is a widely used means for regulating the function of Puf family members [ 87 , 89 , 90 ] and other classes of mRNA-binding proteins [ 91 , 92 , 93 ].…”

Aprepitant Promotes Caspase-Dependent Apoptotic Cell Death and G2/M Arrest through PI3K/Akt/NF-κB Axis in Cancer Stem-Like Esophageal Squamous Cell Carcinoma Spheres

“…Earlier research has shown that aprepitant prevented cell proliferation in G2/M and significantly downregulated cyclin B1, as well as upregulated p21 in oral squamous cell carcinoma lines (WSU-HN6, UM1, SCC25, and WSU-HN4) [ 29 – 31 ]. Furthermore, the protein behavior can be altered due to posttranslational modifications such as phosphorylation, sulfation, and glycation, which change a local charge of the protein region [ 32 , 33 ]. Therefore, many changes in gene expression recorded between experiment groups are due to posttranslational modifications, not detected by analyses of RNA.…”

Modeling microRNA-driven post-transcriptional regulation by using exon-intron split analysis (EISA) in pigs

“…Although miRNAs were the major post-transcriptional regulators that we considered in this study, it is important to remark that other additional post-transcriptional modifications and interactions might be responsible for the observed downregulation of mRNAs. For instance, long non-coding RNAs [57], circular RNAs [58,59], RNA methylation [60] or RNA binding proteins [61–63] can all act as post-transcriptional regulators of targeted mRNAs. We further hypothesized that genes showing relevant post-transcriptional downregulatory effects might be regulated by the same set of significantly upregulated miRNAs, which could induce shared covariation in their expression profiles at the exonic level.…”