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The Hnrnp Family: Insights Into Their Role in Health and Disease

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The Hnrnp Family: Insights Into Their Role in Health and Disease Hum Genet DOI 10.1007/s00439-016-1683-5 REVIEW The hnRNP family: insights into their role in health and disease Thomas Geuens1,2 · Delphine Bouhy1,2 · Vincent Timmerman1,2 Received: 23 March 2016 / Accepted: 9 May 2016 © The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Heterogeneous nuclear ribonucleoproteins MBP Myelin basic protein (hnRNPs) represent a large family of RNA-binding pro- NF Neurofilament teins (RBPs) that contribute to multiple aspects of nucleic NLS Nuclear localization signal acid metabolism including alternative splicing, mRNA sta- PTBP1 Polypyrimidine tract-binding protein 1 bilization, and transcriptional and translational regulation. qRRM Quasi RNA recognition motif Many hnRNPs share general features, but differ in domain RBD RNA-binding domain composition and functional properties. This review will RBP RNA-binding protein discuss the current knowledge about the different hnRNP RGG box Arg-Gly-Gly box family members, focusing on their structural and functional RNP Ribonucleoprotein divergence. Additionally, we will highlight their involve- RRM RNA recognition motif ment in neurodegenerative diseases and cancer, and the SMA Spinal muscular atrophy potential to develop RNA-based therapies. SMN Survival motor neuron snRNP Small nuclear ribonucleoprotein Abbreviations TGF-β Transforming growth factor-beta A2RE A2 response element UTR Untranslated region AD Alzheimer’s disease 15-LOX 15-Lipoxygenase ALS Amyotrophic lateral sclerosis APP Amyloid precursor protein Dab2 Disabled-2 Introduction EMT Epithelial–mesenchymal transition FTLD Fronto-temporal lobe dementia Many ribonucleoproteins (RNPs) assemble on to newly hnRNP Heterogeneous nuclear ribonucleoprotein created transcripts in the nucleus of a eukaryotic cell. HPV-16 Human papillomavirus type 16 Among these RNPs are the heterogeneous nuclear ribo- ILEI Interleukin-like EMT inducer nucleoproteins (hnRNPs). They assist in controlling the IRES Internal ribosome entry site maturation of newly formed heterogeneous nuclear RNAs KH K-Homology (hnRNAs/pre-mRNAs) into messenger RNAs (mRNAs), stabilize mRNA during their cellular transport and con- * Vincent Timmerman trol their translation. Considering their functional diversity [email protected]‑ua.be and complexity, hnRNPs act as key proteins in the cellular nucleic acid metabolism (Fig. 1) (Dreyfuss et al. 1993). 1 Peripheral Neuropathy Group, VIB Molecular Genetics The role of hnRNPs in regulating gene expression has Department, University of Antwerp-CDE, Parking P4, Building V, Room 1.30, Universiteitsplein 1, 2610 Antwerp, gained an increasing interest in disease research. The Belgium expression level of hnRNPs is altered in many types of 2 Neurogenetics Laboratory, Institute Born Bunge, University cancer, suggesting their role in tumorigenesis. In addi- of Antwerp, Antwerp, Belgium tion to cancer, many hnRNPs were also linked to various 1 3 Hum Genet neurodegenerative diseases, such as spinal muscular atro- Fig. 1 The diverse nuclear and cytoplasmic functions of hnRNPs. ▸ phy (SMA), amyotrophic lateral sclerosis (ALS), Alz- The hnRNPs have been found to be involved in different stages of the mRNA metabolism. They constantly undergo a binding and release heimer’s disease (AD) and fronto-temporal lobe demen- from their target mRNAs depending on the modification needed. The tia (FTLD). As neurons are non-dividing cells, therefore hnRNPs bind, together with several transcription factors and other needing a tight regulation of mRNA homeostasis, they are RBPs, to promotor and enhancer sequences to direct transcription (1). highly vulnerable to dysfunction of RNA-binding proteins As soon as a part of the newly formed transcript is released by the RNA polymerase II, the hnRNPs and snRNPs bind rapidly to their (RBPs), including the hnRNPs. nascent transcript to stabilize it (2). Once the correct RBP complexes Because of the growing repertoire of different types of are formed, intronic sequences are removed by the spliceosome. RBPs, it is still unclear how and when they are triggered Many hnRNPs are known to regulate alternative splicing leading to to interact and functionally complement each other. The exon skipping or intron retention (3). Mature mRNAs are stabilized by the binding of several types of RBPs, including hnRNPs, which hnRNPs were initially categorized according to their RNA- are found necessary for export through the nuclear pore complex binding domains (RBDs) composition (Dreyfuss et al. 1993), (NPC) and its transport through the cytoplasm until translation initi- but this classification is not exclusive and many different ates (4). As hnRNPs have the capacity to bind to the 3′- and 5′-UTRs hnRNPs share common features. This review will focus on of mRNAs, they can control translational repression or enhancement. Depending on the composition of complexes at the sites where trans- the “standard” hnRNPs (Han et al. 2010) (Fig. 2), discuss the lation initiation factors assemble, the choice to start translation or not overall features of the hnRNP family and highlight their mul- will be made (5). Please note that not all different hnRNP subgroup tifunctionality in cellular homeostasis in health and disease. members are involved in every nuclear or cytoplasmic function. The different hnRNPs are color coded, but do not represent specific hnRNP members The hnRNP family The 40S core particle was the first mRNA–protein complex, two conserved RNP1 octameric and RNP2 hexameric isolated by sucrose density gradients, which comprised sequences that are positioned approximately 30 residues hnRNPs A/B and C (Beyer et al. 1977). Later on, several apart from each other (Dreyfuss et al. 1988). It is known other hnRNPs were identified as RBP complexes via pull- that the variable loops, connecting the β-sheets, contribute down and UV-cross-linking experiments (van Eekelen et al. to its RNA-binding specificity (Görlach et al. 1992). 1981). These complexes were shown to be created out of The RGG box is characterized by contiguous clusters 20 major types of hnRNPs (Table 1) and minor hnRNPs, containing aromatic Phe and Tyr residues intercalated where the latter ones have been found to be less expressed between tripeptide repeats of Arg-Gly-Gly amino acids and do not have hnRNA-binding capacities, but may regu- (Kiledjian and Dreyfuss 1992). The glycine-rich domain is late major hnRNPs (Dreyfuss et al. 1993). often seen as an auxiliary domain, responsible for homol- The functions of hnRNPs vary according to their cellular ogous and heterologous interactions with other hnRNPs localization. The mechanisms that regulate the nucleo-cyto- (Cartegni et al. 1996). plasmic shuttling are, therefore, of extreme importance. The KH domain is originally found in hnRNP K (KH; Most of the hnRNP proteins possess a conventional nuclear K-Homology) as triple repeats (Siomi et al. 1993). All KH localization signal (NLS) and are predominantly present in domains present in hnRNPs are characterized by three- the nucleus during steady state. They are able to translo- stranded antiparallel β-sheet packed against three α-helices cate in the cytosol upon post-translational stimulation or by (βααββα). A flexible loop that links two α-helices in the the recruitment of other hnRNPs (Fig. 1) (Han et al. 2010). KH core specifically interacts with RNA (Fig. 3) (Jensen The hnRNP proteins frequently undergo post-translational et al. 2000). The KH domains are split into two divisions modifications, leading to changes in biological activity and based on their N- or C-terminal extensions. Type I KH subcellular localization. Reported post-translational modi- domains have a βα extension in their C-terminus, whereas fications on hnRNPs include methylation, phosphorylation, Type II KH domains have an αβ extension in their N-termi- ubiquitination and sumoylation (Chaudhury et al. 2010a). nus (Grishin 2001). Next to RBDs, hnRNPs frequently contain auxiliary Structure domains, such as proline-, glycine- or acid-rich domains (Dreyfuss et al. 2002). Not all RBDs are exclusive and the Four unique RBDs were identified in hnRNP proteins: the specificity in RNA binding is largely mediated by the 3D RNA recognition motif (RRM), the quasi-RRM, a glycine- structure of the protein where the structural regions around rich domain constituting an RGG box and a KH domain the RBDs fine-tune the RNA–protein interaction. (Fig. 2). The modularity created by the combination of these dif- The most common RBD is the RNA recognition motif ferent domains including RNA-binding domains (RBDs) (RRM). Eukaryotic RRMs are structurally characterized and auxiliary domains (Fig. 2) increases the functional by four β-sheets and two α-helices (βαββαβ) together with diversity of hnRNPs (Table 1). 1 3 Hum Genet 1 3 Hum Genet Fig. 2 The hnRNP family. The hnRNPs have different molecular binding domains (RBDs). It is obvious that multiple family members weights ranging from 34 to 120 kDa and are named alphabetically carry the same RBDs, partly explaining their shared RNA-binding from hnRNP A1 to hnRNP U. Many hnRNPs are found to be present properties: RRM RNA recognition motif, qRRM quasi-RNA recogni- in the same complexes, all suggesting that multiple hnRNPs share a tion motif and KH K-homology domain, RGG RNA-binding domain common structure and function. As shown in the overview, several consisting of Arg-Gly-Gly repeats. The sizes of these 16 common structural domains are shared between different family members. hnRNPs are drawn relative to each
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