hnRNP A1: the Swiss army knife of gene expression

Abstract

Eukaryotic cells express a large variety of RNA binding proteins (RBPs), with diverse affinities and specificities towards target RNAs. These proteins play a crucial role in almost every aspect of RNA biogenesis, expression and function. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a complex and diverse family of RNA binding proteins. hnRNPs display multiple functions in the processing of heterogeneous nuclear RNAs into mature messenger RNAs. hnRNP A1 is one of the most abundant and ubiquitously expressed members of this protein family. hnRNP A1 plays multiple roles in gene expression by regulating major steps in the processing of nascent RNA transcripts. The transcription, splicing, stability, export through nuclear pores and translation of cellular and viral transcripts are all mechanisms modulated by this protein. The diverse functions played by hnRNP A1 are not limited to mRNA biogenesis, but extend to the processing of microRNAs, telomere maintenance and the regulation of transcription factor activity. Genomic approaches have recently uncovered the extent of hnRNP A1 roles in the development and differentiation of living organisms. The aim of this review is to highlight recent developments in the study of this protein and to describe its functions in cellular and viral gene expression and its role in human pathologies.

Figure 1

Structural features h nuclear ribonucleoprotein (hnRNP) A1. (A) Schematic map of the two hnRNP A1 isoforms. Acetylation (A), phosphorylation (P) and SUMOylation (S) sites are labeled; (B) Schematic representation of hnRNP A1 structural and functional domains.

Figure 2

Splicing regulation mechanisms of hnRNP A1. (A) Serine/arginine-rich (SR) proteins bound to an exonic splicing enhancer (ESE) promote recruitment of splicing factors to nearby splice sites. Binding of hnRNP A1 to an exonic splicing silencer (ESS) overlapping an ESE displaces the SR proteins and promotes skipping of the exon from the mRNA [,–93]; (B) hnRNP A1 binding to a high affinity binding site, which functions as an ESS, promotes cooperative binding of other hnRNP A1 molecules along the transcript. This inhibits the binding of SR proteins and other splicing factors and promotes exclusion of the exon from the mRNA [94]; (C) Binding of hnRNP A1 to an intronic splicing silencer (ISS) overlapping an SR-dependent intronic splicing enhancer (ISE), or the branch point (bp) displaces SR proteins or the U2 snRNP and inhibits splicing of the downstream exon [18,95,96]; (D) The interaction among hnRNP A1 proteins bound to ISS upstream and downstream the alternatively spliced exon promotes looping-out and exclusion of the exon [16,97,98].