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.
Highlights
Gene regulatory networks are constantly tuning mRNA and protein levels according to cellular needs, affecting all steps of the expression process, from transcription to protein degradation, and including mRNA maturation, transport and translation (Adeli, 2011). mRNA molecules are permanently associated with a dynamic set of proteins and non-coding RNAs, such as microRNAs, in the so-called messenger ribonucleoprotein particles
The interaction of most known RNA-binding protein (RBP) with their cognate transcripts is mediated by a small group of RNA-binding domains (RBDs), such as the RNA recognition motif (RRM), K homology (KH), zinc-finger and DEAD/DEAH box helicase
An example of interplay between post-translational modification (PTM) can be found in the nucleo-cytoplasmic shuttling of the KH-type splicing regulatory protein (KSRP). Phosphorylation of this RBP at Ser193 by Akt1 causes the unfolding of its first KH domain, giving rise to a binding site for the chaperone protein 14-3-3ζ, whose interaction is involved in the nuclear confinement observed for the phospho-isoform of KSRP (Díaz-Moreno et al, 2009)
Summary
Gene regulatory networks are constantly tuning mRNA and protein levels according to cellular needs, affecting all steps of the expression process, from transcription to protein degradation, and including mRNA maturation, transport and translation (Adeli, 2011). mRNA molecules are permanently associated with a dynamic set of proteins and non-coding RNAs, such as microRNAs (miRNAs), in the so-called messenger ribonucleoprotein particles (mRNPs). PTMs can dramatically change the subcellular localization, the binding affinity for RNA and protein partners, and the turnover rate of RBPs. the ability of many RBPs to undergo phase transition and/or their recruitment to previously formed membrane-less organelles, such as stress granules, is regulated by specific PTMs. Interestingly, the dysregulation of PTMs in RBPs has been associated with the pathophysiology of many different diseases.
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