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Review
. 2021 Apr 27:8:658852.
doi: 10.3389/fmolb.2021.658852. eCollection 2021.

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

Alejandro Velázquez-Cruz  1 , Blanca Baños-Jaime  1 , Antonio Díaz-Quintana  1 , Miguel A De la Rosa  1 , Irene Díaz-Moreno  1
Affiliations
Review

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

Alejandro Velázquez-Cruz et al. Front Mol Biosci. .

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.

Keywords: FUS; HuR; KSRP; RNA-binding proteins; TIA-1/TIAR; hnRNP K; liquid–liquid phase separation; post-translational modifications.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Examples of PTM-mediated regulation of RBPs. (A) KSRP can shuttle between nucleus (N) and cytoplasm (C) to perform specific functions in each compartment. However, phosphorylation at Ser193 by Akt1, stimulated by growth factors, promotes the translocation of KSRP to the nucleus, whereas hypoxia-induced SUMOylation at Lys83 leads to its nuclear export (Díaz-Moreno et al., 2009; Yuan et al., 2017). (B) Phosphorylation of TIA-1 by FASTK improves its ability to recruit the U1 snRNP spliceosomal complex to the 5′ splice site region of the Fas receptor pre-mRNA exon 6. The resulting mature mRNA will express mFas, which plays an important role in the extrinsic apoptosis signaling pathways. In contrast, splicing of Fas receptor in the presence of unphosphorylated TIA-1 results in exon 6 skipping and the synthesis of sFas, that blocks apoptosis (Förch et al., 2002; Izquierdo and Valcárcel, 2007). (C) Under standard conditions, hnRNP K is targeted by the E3 Ub-ligase HDM2 for proteasomal degradation. Nonetheless, DNA damage triggers ATM-dependent phosphorylation of hnRNP K at Ser121, Thr174, Thr390, and Thr440, thus lowering its turnover rate. In addition, phosphorylated hnRNP K stimulates p53-mediated p21 gene expression, which causes cell cycle arrest (Moumen et al., 2005, 2013).
FIGURE 2
FIGURE 2
Examples of disease-related dysregulation of PTMs in RBPs. Proteins and components involved in homeostatic pathways are depicted in grayscale, except symbols that stand for PTMs. (A) Frontotemporal lobar degeneration (FTLD): FUS molecules can build either droplets or droplets evolving into fibrillary gel state depending on its arginine methylation level, which is controlled by PRMT1 enzymes. Asymmetrically dimethylated FUS yields physiological droplets under homeostatic conditions, whereas hypo-methylated FUS forms highly stable fibrillary gels in FTLD; such fibrillary gels impede normal activity of RNP granules and decrease protein synthesis in neurons (Qamar et al., 2018). (B) Tumor cell proliferation: HuR is translocated from the nucleus (N) to the cytoplasm (C) upon PKCδ-dependent phosphorylation at Ser318, thus increasing the stability of tumor related transcripts such as COX-2 and cyclin-A. Elevated levels of Ser318-phosphorylated HuR have been detected in colon carcinoma (Doller et al., 2011). (C) Coronary artery disease: unphosphorylated NCL can shuttle between cytoplasm (C) and nucleus (N), and participates in the processing of key pri-miRNAs by the Drosha-DGCR8 complex. Such mature miRNAs associate with AGO proteins to activate the miRISC complex and thus guide the degradation of KLF2 and eNOS mRNAs. As a result, nitric oxide levels in endothelial cells decrease, producing vascular dysfunction (Gongol et al., 2019).
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