Roles of RNA-binding proteins in neurological disorders, COVID-19, and cancer

Abstract

RNA-binding proteins (RBPs) have emerged as important players in multiple biological processes including transcription regulation, splicing, R-loop homeostasis, DNA rearrangement, miRNA function, biogenesis, and ribosome biogenesis. A large number of RBPs had already been identified by different approaches in various organisms and exhibited regulatory functions on RNAs' fate. RBPs can either directly or indirectly interact with their target RNAs or mRNAs to assume a key biological function whose outcome may trigger disease or normal biological events. They also exert distinct functions related to their canonical and non-canonical forms. This review summarizes the current understanding of a wide range of RBPs' functions and highlights their emerging roles in the regulation of diverse pathways, different physiological processes, and their molecular links with diseases. Various types of diseases, encompassing colorectal carcinoma, non-small cell lung carcinoma, amyotrophic lateral sclerosis, and Severe acute respiratory syndrome coronavirus 2, aberrantly express RBPs. We also highlight some recent advances in the field that could prompt the development of RBPs-based therapeutic interventions.

Keywords: Cancer; Neurodegenerative diseases; Post-transcriptional gene regulation; RNA; RNA processing; RNA-binding proteins; Viral infection.

Fig. 1

Typical domains observed in RNA-binding proteins. A Schematic representation of IMP3 domains. All tandem RBDs are endorsed with RNA-binding activities. RRM1 and RRM2 recognize CA-rich and CA repeats sequences in RNA. KH1-2 specifically recognizes GGC-CA or CA-GGC motifs in RNAs. KH3-4 identify GGC-CA motifs in RNAs [2]. B Schematic representation of IGF2BP domains. All tandem RBDs are identified but only KH domains are specifically used to recognizes m6A-modified mRNAs [3]. C Schematic representation of hnRNP A2/B1 domains with known residue numbers. RNA-binding domain (RBD) composed of tandem RRMs separated by a 15-aa linker, and a C-terminal Gly-rich low complexity (LC) region that includes a prion-like domain (PrLD), an RGG box: arginine-glycine-glycine box, and a PY-motif containing a M9 nuclear localization signal (PY-NLS). RRM1 specifically recognizes AGG motif in RNAs. RRM2 specifically recognizes UAG motif in RNAs but also purine-rich GAG, and pyrimidine-rich UU sequences [4]. D Schematic representation of TDP-43 RRM domains. 414-residue TDP-43 includes: N-terminal domain (NTD) over residues 1–80; two tandemly-tethered RNA recognition motifs (RRM1 and RRM2) over residues 105–261 connected by an unstructured linker over residues 181–192, and C-terminal prion-like domain over residues 274–414 [5]

Fig. 2

Numerous cellular events and disease processes regulated by RNA-binding proteins. The RBP PUM1 binds the 3´-untranslated region of Toll-like receptor 4 (TLR4) to clear TLR4 mRNA translation and monitor the activity of nuclear factor-κB (NF-κB), a master regulator of the aging process in human mesenchymal stem cells. PUM1 also protects human chondrocytes to avoid chondrogenic phenotype loss and alleviates cellular osteoarthritis [29]. The loss of functional RBP muscle blind-like protein 1 (MBNL1) in response to its nuclear seclusion by mutant transcripts containing pathogenic expanded CUG repeats (CUGexp) leads to Myotonic dystrophy type 1 [30]. Mitochondrial RNA-binding protein tumor necrosis factor receptor-associated protein 1 (TRAP1)-associated, chaperone-mediated autophagy can stimulate ferroptosis [31]. The RBP human antigen R (HuR) translocation into the cytoplasm orchestrates by its interaction with circular RNAs circStag1 is involved in the regeneration of bone tissue [32]. Inclusion of the RBP TDP-43-regulated alternative exons is altered in skeletal muscles of patients with inclusion body myositis (IBM, [27]). RBP ZFP36 and ZFP36L1 bind transcripts encoding subunits of the NF-κB pathway, Notch1, Irf8 and Il2 to monitor the abundance of their protein products early after activation in CD8 + T cells [33]. Heterozygous frameshift variants in the RBP hnRNPA2/B1 do not augment the propensity of hnRNPA2 protein to fibrillize but diminished affinity for the nuclear import receptor karyopherin β2, leading to cytoplasmic accumulation of hnRNPA2 protein in cells and early-onset form of oculopharyngeal muscular dystrophy [34]. HNRNPC (heterogeneous nuclear ribonucleoprotein C) associated with the newly identified regulator of ferroptosis in Colorectal cancer, CUL9, for resistance to drug-induced ferroptosis [35]. The RBP heterogeneous nuclear ribonucleoprotein RBP (hnRNPH1) is essential for pre-mRNA alternative splicing, spermatogenesis and oogenesis [36]. RBP Tardbp is an important candidate monitoring alternative splicing and alternative polyadenylation to optimize clonal expansion and human CD8 + T cells effector function during an antigen-specific immune response [37]. In embryonic stem cells, RBPs represent half of the chromatin proteome, co-compartmentalize with RNA polymerase (Pol) II at promoters and enhancer, and connect RNA to the transcription machinery [38]. The RBP DDX41 is a tumor suppressor that opposes double-strand DNA breaks, genomic instability and R-loop-dependent replication stress by preferentially binding RNA–DNA hybrids and unwinding RNA–DNA hybrids in R-loops, and also reduces fragility of DNA in promoter regions [39]. RBP HNRNPC is demonstrated to interact with circXRCC5 to encourage circXRCC5 biogenesis that was proved to foster Gastric cancer progression [40]. By binding to hTERT (reverse transcriptase protein catalytic subunit hTERT) mRNAs in intron 8, the RBP NOVA1 (neuro-oncological ventral antigen 1) acts as a splicing enhancer that promotes the inclusion of exons 7 and 8 to enhance the production of full-length (FL) hTERT mRNAs in non-small cell lung cancer cells [41]. The RBP “partner of NOB1” (PNO1)-mediated ribosome biogenesis is negatively regulated by miR-340-5p directly binds the 3′-UTR of PNO1 and assumes an important role in LUAD progression via Notch signaling pathway [42]. RBP (ROD1, so-called PTBP3) interacts with Activation-induced cytidine deaminase (AID), which jointly bind bi-directionally transcribed RNAs to facilitate genome-wide AID targeting to immunoglobulin (Ig) loci in a way to induce DNA rearrangement during immune responses [43]. The RBP KHSRP regulates cell proliferation and cell cycle in Wilms tumor by modulating the expression of PPP2CA and p27 [44]

Fig. 3

Architecture of typical RNA-binding proteins with low complexity domain localized in intrinsically disordered proteins. The figure highlighted RNA recognition motifs 1 and 2 (RRM1 and RRM2), a low complexity domain (LCD), and a nuclear localization signal (NLS) within the LCD. Missense mutations (G287S, A315T, G348C, R361S, A382T, N390D, N390S) in LCD are responsible for amyotrophic lateral sclerosis [81]. Pathogenic mutations (c.785/941A.T, p.D262V/D314V in hnRNPA1 and c.869/905A.T, p.D290V/D302V in hnRNPA2B1) in prion-like domains of hnRNPA2B1 and hnRNPA1 are responsible for multisystem proteinopathy (MSP; [34]. Missense mutations (P362L, A381T, and E384K) impacting the LCD of the RNA-binding protein T cell-restricted intracellular antigen-1 (TIA1) drive ALS and Frontotemporal Dementia (FTD) [82]. RBMX’s low-complexity region consists of a serine and arginine-rich region (SRR) followed by a tyrosine-rich region (TRR) is required for monitoring the expression of CBX5 mRNA encoding CBX5 protein in the hematological malignancy acute myeloid leukemia (AML) cells [83]