Several RNA-binding proteins have one or more paralogs, i.e. a related protein produced by gene duplication. Paralogous proteins often share high sequence similarity and address a strongly overlapping set of target genes. Despite the general tendency of paralogs to act redundantly, individual paralogs possess unique cellular functions by addressing different target genes.
Due to the versatile functions of RNA-binding proteins, precise regulation of their expression is crucial to prevent the onset and progression of pathological processes. Homeostasis at the protein level is often achieved by negative feedback loops. Thus, the RNA-binding protein controls its own expression by binding directly to its own transcript. A common mechanism for such control is AS-NMD. It couples alternative splicing (AS) to nonsense-mediated decay (NMD) by targeted production of mRNA isoforms containing NMD characteristics, i.e. a stop codon ˃50-55 nt upstream of an exon-junction. AS-NMD is not only used for autoregulation, but also for cross-regulation between two RNA-binding proteins.
We identified an intricate cross-regulation between the paralogs hnRNP D and DL (Fig. 1). Both are able to control their own expression by alternative splicing of cassette exons in their 3’UTRs (3’ untranslated regions). Exon inclusion produces mRNA isoforms that are degraded by NMD. In addition, hnRNP D and DL control the expression of each other by the same mechanism (Fig. 2). This close interconnection of expression control directly links hnRNP DL to hnRNP D-related diseases and underlines the importance of systematic analysis of its cellular function. Future research will aim to understand the physiological role of hnRNP DL, to identify its direct target genes and to define redundant and unique molecular functions in relation to hnRNP D.