hnRNP A1 in RNA metabolism regulation and as a potential therapeutic target

Abstract

Abnormal RNA metabolism, regulated by various RNA binding proteins, can have functional consequences for multiple diseases. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is an important RNA binding protein, that regulates various RNA metabolic processes, including transcription, alternative splicing of pre-mRNA, translation, miRNA processing and mRNA stability. As a potent splicing factor, hnRNP A1 can regulate multiple splicing events, including itself, collaborating with other cooperative or antagonistical splicing factors by binding to splicing sites and regulatory elements in exons or introns. hnRNP A1 can modulate gene transcription by directly interacting with promoters or indirectly impacting Pol II activities. Moreover, by interacting with the internal ribosome entry site (IRES) or 3'-UTR of mRNAs, hnRNP A1 can affect mRNA translation. hnRNP A1 can alter the stability of mRNAs by binding to specific locations of 3'-UTR, miRNAs biogenesis and Nonsense-mediated mRNA decay (NMD) pathway. In this review, we conclude the selective sites where hnRNP A1 binds to RNA and DNA, and the co-regulatory factors that interact with hnRNP A1. Given the dysregulation of hnRNP A1 in diverse diseases, especially in cancers and neurodegeneration diseases, targeting hnRNP A1 for therapeutic treatment is extremely promising. Therefore, this review also provides the small-molecule drugs, biomedicines and novel strategies targeting hnRNP A1 for therapeutic purposes.

Keywords: RNA binding protein; RNA metabolism; alternative splicing; hnRNP A1; splicing factor.

FIGURE 1

A scheme of the hnRNP A1 primary amino acids sequence (UniProt:P09651-2). The amino acids (1–196) are the N-terminus (also named UP-1) of hnRNP A1, consisting of two RNA recognition motifs (RRM1 and RRM2, Yellow). The amino acids sequences of dark gray are the C-terminus (also named GRD,197–320), composed of RGG (197–249, Green) with four RGG motifs (Italic Bold), M9 (268–305, Red) and F-peptide (301–319, Italic Underline). The phosphorylation and poly (ADP-ribosylation) sites of hnRNP A1 are marked.

FIGURE 2

Schematic representation of the human pre-PKM gene and the regulation of its mutually exclusive alternative splicing. Exon9 (E9) and Exon10 (E10) of PKM gene are two mutually exclusive exons. Generation of the PKM1 isoform using E9 is crucial for tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation producing maximum ATP. PKM2, including E10 but not E9, results in aerobic glycolysis (the Warburg effect) with high lactate production, contributing to AD, myocardial infarction and cancer progression. hnRNP A1 (Highlighted in Green) suppresses the E9 inclusion by binding to 5′ SS downstream E9 and co-regulation with cooperative factors (hnRNP A2, hnRNP I, SRSF3, SAM68, NEK2 and HIF1) and antagonistic factor (RBMX and RBM4).

FIGURE 3

The multifaceted roles of hnRNP A1 in mRNA metabolism. hnRNP A1 affects gene transcription through binding to 7SK snRNA or directly binding to the gene promoter; hnRNP A1 can be recruited to the m6A-modification, and act as a m6A “reader” to promote the transcription. hnRNP A1 enhances mRNA stability through binding to specific sites of 3′-UTR. hnRNP A1 also contributes to the biogenesis of miRNAs, and then the specific miRNAs suppress the mRNA translation or targeting the mRNA decreasing the stability. hnRNP A1 regulates alternative splicing events by binding to specific splice sites and splicing regulatory elements, as well as interacting with cooperative or antagonistic splicing factors. hnRNP A1 increases gene translation by binding to G-quadruplex, and shows positive or negative effects when using its ITAF activity binding to IRES sequence or binding to 3′-UTR of mRNAs.