Systematic Analysis of Gene Expression Profiles Controlled by hnRNP Q and hnRNP R, Two Closely Related Human RNA Binding Proteins Implicated in mRNA Processing Mechanisms

Abstract

Heteregeneous ribonucleoproteins (hnRNPs) are a family of RNA-binding proteins that take part in all processes that involve mRNA maturation. As a consequence, alterations of their homeostasis may lead to many complex pathological disorders, such as neurodegeneration and cancer. For many of these proteins, however, their exact function and cellular targets are still not very well known. Here, we focused the attention on two hnRNP family members, hnRNP Q and hnRNP R, that we previously found affecting TDP-43 activity both in Drosophila melanogaster and human neuronal cell line. Classification of these two human proteins as paralogs is suported by the high level of sequence homology and by the observation that in fly they correspond to the same protein, namely Syp. We profiled differentially expressed genes from RNA-Seq and generated functional enrichment results after silencing of hnRNP Q and hnRNP R in neuroblastoma SH-SY5Y cell line. Interestingly, despite their high sequence similarity, these two proteins were found to affect different cellular pathways, especially with regards to neurodegeneration, such as PENK, NGR3, RAB26, JAG1, as well as inflammatory response, such as TNF, ICAM1, ICAM5, and TNFRSF9. In conclusion, human hnRNP Q and hnRNP R may be considered potentially important regulators of neuronal homeostasis and their disruption could impair distinct pathways in the central nervous system axis, thus confirming the importance of their conservation during evolution.

An epilepsy-associated mutation in the nuclear import receptor KPNA7 reduces nuclear localization signal binding

“…Our analysis found a significant enrichment of proteins involved in RNA and mRNA processing, including hnRNP R and hnRNP U. We validated the biochemical interactions of KPNA7 with hnRNP R and hnRNP U, and we also determined the importance of putative mono-and bipartite NLS sequences in these hnRNPs 42,43 . We found that the E344Q substitution in KPNA7 reduced binding and transport mediated by the NLS in hnRNP R and hnRNP U.…”

“…Based on protein sequence analysis and its similarity to the closely related hnRNP Q, hnRNP R was proposed to contain both a monopartite NLS (mNLS, a.a. 412-418) and a bipartite NLS (bNLS, a.a. 565-589) ( Fig. 4a) 42,43 . The necessity and sufficiency of these NLSs in hnRNP R, however, have not been tested.…”

Comprehensive in vivo identification of the c-Myc mRNA protein interactome using HyPR-MS

“…HNRNPR modulates cap-independent translation rates in the cytosol by linking target mRNA IRESs (Geuens et al 2016). Finally, HNRNPR and SRSF1 have been reported in mRNA stabilization (Lemaire et al 2002;Sun et al 2011;Cappelli et al 2018) and could play this role for c-Myc transcripts as well.…”

The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis

“…Of note, there has been a little emphasis from any study in determining the potentially different roles of the separate isoforms of these proteins. Given that it appears different R and Q isoforms may serve distinct, non-redundant cellular functions [23], it will be important to establish whether they also play different roles in disease pathogenesis.…”

“…Further functions of hnRNP Q include the post-transcriptional modulation of circadian clock gene mRNAs levels [ 94 , 95 ], morphological development of neuromuscular junctions [ 194 ] and the exosomal sorting of specific micro RNAs [ 72 ]. Both hnRNP R and Q have been identified as potentially important regulators of neuronal homeostasis and cellular pathways associated with neurodegeneration [ 23 ].…”