M I N I R E V I E W
TDP-43: new aspects of autoregulation mechanisms in RNA binding proteins and their connection with human disease Emanuele Buratti and Francisco E. Baralle
International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
Keywords alternative splicing; autoregulation; hnRNP; mRNA stability; NMD; SR proteins; TDP-43
Correspondence F. E. Baralle, Padriciano 99, 34012 Trieste, Italy Fax: +39 040 375 7361 Tel: +39 040 375 7337 E-mail: baralle@icgeb.org
(Received 4 February 2011, revised 8 April 2011, accepted 28 April 2011)
doi:10.1111/j.1742-4658.2011.08257.x
The maintenance of correct protein homeostasis (‘proteostasis’) is an essen- tial activity of mammalian cells to preserve their vital properties and func- tions. Because of its importance, correct proteostasis is achieved by the cell in several ways and at several levels of each gene expression pathway. In many cases, mRNA-autoregulatory pathways based on a variety of feed- back mechanisms have been observed to play a major role in keeping their concentration under control. This is especially true for RNA binding pro- teins because of their potential ability to bind their own pre-mRNA mole- cules, and in particular for two subsets of nuclear factors that are commonly referred to as heterogeneous ribonucleoproteins and serine–argi- nine-rich proteins. Regarding the mechanism, nonsense-mediated RNA degradation triggered by alternative splicing of their own messenger RNA is a very common autoregulation pathway to maintain constant expression levels within the cellular environment. Recently, however, alternative mech- anisms other than nonsense-mediated decay have also been described to play a role for other RNA binding protein factors: serine–arginine-rich splicing factor 1 (SRSF1) and transactive response DNA binding protein 43 kDa (TDP-43). The aim of this minireview will be to discuss these old and new autoregulatory processes and their implication in disease develop- ment.
Introduction
With the term ‘proteostasis’ researchers have recently started referring to the ability of a cell to maintain cor- rect protein concentration levels, folding, secondary interactions, and localization within the various cellu- lar compartments [1]. For obvious reasons, maintain- ing a healthy proteome is of fundamental importance for the well-being of the cell and for its ability to ade- quately perform its intended role in the life of an
organism. Indeed, the age-progressive inability of a cell to maintain a correct proteostasis is now beginning to be recognized as a fundamental component of many diseases, especially at the neuronal level [2]. As can be expected for such an important process, several differ- ent mechanisms contribute to maintaining a healthy proteome. These mechanisms have been observed to act at all levels of the protein expression cycle, starting
Abbreviations hnRNP, heterogeneous ribonucleoprotein; NMD, nonsense-mediated decay; PTB, polypyrimidine tract binding; RBP, RNA binding protein; RRM, RNA recognition motif; RUST, regulated unproductive splicing and translation; SR, serine–arginine-rich; SRSF1, serine–arginine-rich splicing factor 1; TDP-43, transactive response DNA binding protein 43 kDa; TDPBR, TDP-43 binding region; Tra2, transformer 2.
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can potentially mediate common pathways to regulate their expression within the cell [23–25]. From a func- tional point of view, these sequences have often been associated with alternative splicing events (either skip- ping or ‘poison’ exon inclusion) that can trigger non- sense-mediated RNA degradation [26]. Recently, the general term RUST (for regulated unproductive splic- ing and translation) has been coined for this particular regulation pathway [27]. Notably, RUST has been shown to potentially apply for a substantial fraction of all alternative splicing events occurring in humans [27].
stability, export,
Nonsense-mediated decay (NMD) autoregulatory mechanisms
[33] and transformer 2 (Tra2)
functional
their
stability and internal
from basic gene transcription regulation and ending in the recognition ⁄ transport of the correctly translated and folded protein at its intended destination and in the rightful amounts [1]. Among these various check- point levels, a very important regulatory step of pro- tein production has long been known to exist at the RNA processing stage. In the eukaryotic cell several hundred RNA binding proteins (RBPs) regulate all aspects of this pathway by affecting all stages of an mRNA life-cycle: capping and polyadenylation steps, constitutive and alternative splicing process, editing steps, transport, and localization [3–5]. With regard to the proteins involved in these regulatory pathways, one of the most abundant classes of RBPs in the human nucleus is represented by the so-called heterogeneous ribonucleoprotein (hnRNP) factors that are responsible for forming the core of many ribonucleoprotein complexes [6–9]. The hnRNPs are a class of loosely related proteins that share a number of basic characteristics (mainly the presence of RNA recognition motifs (RRMs) [10] used to bind RNA in a sequence-specific manner and of a Gly-rich region important for mediating protein–protein inter- actions). They are composed of a core of (cid:2) 20 very abundant factors (called A1 to U) and are important players in all aspects of RNA metabolism: the packag- ing of the nascent transcript, the regulation of alterna- tive splicing processes, transport, and eventually in translational control [11]. Another class of RBPs that is important for RNA metabolism is represented by the serine–arginine-rich (SR) proteins that are charac- terized by the presence of a serine–arginine-rich region in their C-terminal regions (hence the name) [12]. His- torically, SR proteins are best known in relationship to their ability to work antagonistically to hnRNPs in regulating splicing processes [13,14]. In recent years, however, role has been greatly expanded by the observations that several members of this class of factors play important roles in various processing events that include transcription, genome stability, mRNA transport and translation [15,16]. As a consequence, beside the role played by these factors in aberrant pre-mRNA splicing events [17,18], both hnRNP and SR proteins have been shown to play important roles in various pathological conditions, especially with regard to cancer development and neu- rodegenerative diseases [19–22].
Autoregulatory pathways in hnRNP and SR or SR-like proteins have already been described for polypyrimi- dine tract binding protein (also known as PTB or hnRNP I) [28], hnRNP L [29], hnRNP A ⁄ B family members [30], TIA-1 ⁄ TIAR [31], SRFS3 (SRp20) [32], SRFS2 (SC35) [34] (although in this particular case the simple introduc- tion of a translational block due to a frame change fol- lowing exon 2 inclusion in the mature Tra2 mRNA may account for autoregulation). In the case of PTB, the basic regulatory mechanism is the alternative skip- ping of exon 11 that leads to mRNA degradation through NMD activation (Fig. 1). The exon 11 skip- ping process is triggered by PTB through its binding to the upstream intron of exon 11. This gives rise to a negative feedback loop that can function to prevent the synthesis of excessive PTB protein levels or to restore normal nuclear levels when this factor is mobi- lized in the cytoplasm [28]. Another hnRNP factor in which autoregulation works in a similar way is repre- sented by hnRNP L. Like PTB, this is a multifunction- al hnRNP protein that plays a role in mRNA splicing, ribosome entry site export, (IRES)-mediated translation. In this case, however, the increase in cellular levels of hnRNP L promote the inclusion of a ‘poison’ exon (6a), rather than resulting in particular exon skipping like PTB exon 11. Inclu- sion of this exon leads to degradation by NMD of the resulting messenger and thus reduction of hnRNP L production levels (Fig. 2). In a similar situation to that of PTB, increased inclusion of this poison exon is med- iated by hnRNP L binding to enhancer elements in the upstream intron [29]. It should be noted, however, that very often these seemingly straightforward autoregula- tory pathways are embedded in other cross-regulatory interactions that involve closely related proteins such as hnRNP LL [29] and nPTB [35]. Therefore, it should always be kept in mind that even these apparently
Because of their great importance, the expression of these hnRNP and SR factors is under very tight con- trol by the cellular regulatory machinery. This conclu- sion is supported by a variety of studies that have highlighted the presence of ultraconserved sequences within selected introns of many of these families that
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1312 nt.
1220 nt.
457 nt.
Fig. 1. PTB autoregulation. This figure shows a schematic diagram of the autoregu- latory process of PTB. This process is based on the promotion of exon 11 skipping fol- lowing the binding of PTB to the upstream exon. The resulting (11)) transcript is then selectively degraded by NMD.
603 nt.
745 nt.
1080 nt.
3282 nt.
1225 nt.
2265 nt.
1545 nt.
114 nt.
295 nt.
117 nt.
93 nt.
111 nt.
Fig. 2. hnRNP L autoregulation. The hnRNP L factor can autoregulate its own expression levels by binding to the intronic region upstream of ‘poison exon’ 6a and triggering its inclusion in the mature mRNA. The mature mRNAs carrying exon 6a are then selectively degraded by the NMD machinery, thus lowering the amount of hnRNP L expression when cellular levels are critically high.
Additional autoregulatory mechanisms other than NMD
As described above, most autoregulatory mechanisms described in the literature dealing with RBPs mainly rely on a close coupling between the activation of par- ticular alternative splicing events and NMD. It is now becoming clear, however, that other additional mecha- nisms may be active in mediating autoregulation. For
simple autoregulation pathways in the ‘real’ environ- ment are often regulated by a very complex network of related and unrelated proteins that can promote similar events. Finally, it should be noted that this kind of autoregulatory mechanism is certainly not con- fined to humans since it has also been reported that Drosophila HRP59 protein (the fly homologue of hnRNP M) can also autoregulate its expression levels through alternative splicing of its own pre-mRNA [36].
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Fig. 3. SRSF1 autoregulation. The SR protein SRSF1 can autoregulate its own expression levels by both regulating the amount of NMD-sensitive mRNAs produced from the transcribed pre-mRNA molecule (1) and inhibiting translation of the coding mRNAs at the ribosomal level (2). Both inhibitory processes are increased following SRSF1 overexpression within cells. For both processes to take place the 3¢UTR sequence of the SRSF1 mRNA is essential. The exact mechanism used to achieve these two aims is currently unknown although translation inhibition has been determined not to depend on the cap structure and to involve, at some stage, eIF2 and ⁄ or eIF3.
In this case,
A schematic diagram of this autoregulatory process is reported in Fig. 4. Of course, exactly the opposite effect should be achieved in the event that TDP-43 levels within the cell were to drop under the natural threshold. increased mRNA stability and lower exosome degradation would cause TDP-43 levels to rise again.
example, in the case of the serine–arginine-rich splicing factor 1 (SRSF1, former SF2 ⁄ ASF [37]) it has recently been reported that several mechanisms can act together to finely tune the amount of this protein made inside the cell. In the recent model proposed by Sun et al. [38], beside playing a role in the generation of NMD- sensitive splicing isoforms the 3¢UTR region of this gene is instrumental in enhancing repression of its translation by the ribosomal machinery (Fig. 3).
is
In addition to this main mechanism, the work by Ayala et al. [42] also describes the existence of a minor is regulated by NMD. that TDP-43 isoform (V2) Furthermore, the interaction of TDP-43 with its own 3¢UTR region has been confirmed by two recent stud- ies using crosslinking and immunoprecipitation (CLIP) analyses [43–45]. In particular, the analyses of Poly- menidou et al. [44] have also confirmed the NMD autoregulation of the V2 transcript (referred to as iso- form 3 in their study). In contrast with what has been argued in the Polymenidou et al. paper, however, it is unlikely that this NMD-degraded isoform may have a significant role in TDP-43 autoregulation as it is expressed to very low levels even in the presence of CHX or following Upf1 knockdown and its levels do not change upon overexpression of TDP-43 [42].
Finally,
Another example in which NMD mechanisms do not seem to play a very important role is represented by the TDP-43 protein. Transactive response DNA- binding protein 43 a ubiquitously (TDP-43) expressed protein belonging to the hnRNP family and containing two RRM domains and a glycine-rich C-terminal tail required for protein–protein interaction [39–41]. In the case of TDP-43, autoregulation seems to occur through a particular region of its highly con- is called the TDP-43 binding served 3¢UTR that region (TDPBR). This region has been found to con- tain a certain number of relatively low affinity binding sites for TDP-43 scattered within a region (cid:2) 700 nucleotides long. When TDP-43 nuclear levels rise, increased binding to the TDPBR promotes mRNA instability and may also cause other effects at the level of RNA pol II processivity (stalling) or termination defects [42]. The exosome system has also been dem- onstrated to be important in reducing the levels of TDP-43 mRNA when TDP-43 is abundant in the cell.
it should be mentioned that these recent CLIP analyses [43–45] have detected binding of TDP-43 to many 3¢UTR sequences of various human and suggesting that TDP-43 binding to mouse genes 3¢UTR sequences may act as a general regulator of gene expression.
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972 nt.
2878 nt.
1725 nt.
1555 nt.
1524 nt.
1
Fig. 4. TDP-43 autoregulation. The autoreg- ulatory process of TDP-43 is mostly NMD- independent and relies on its particularly long and highly conserved 3¢UTR region. In particular, its action depends on a 700-long sequence called TDPBR (TDP-43 binding region) localized (cid:2) 700 nucleotides from the ‘tag’ stop codon. Binding of excess TDP-43 to this region causes the resulting mRNAs to lose stability. The exosome system, when impaired, has also been demonstrated to be important in reducing the levels of TDP-43 mRNA under overexpression condi- tions. Other defects at the level of transcrip- tion rate (RNA PolII stalling) or termination are also possible and may contribute to some extent.
Disruption of autoregulatory processes and human disease
aberrant phosphorylation) or loss-of-function effects (due to its absence from the nucleus with the conse- quent disruption of TDP-43-controlled processes such as transcription, alternative splicing, mRNA transport, microRNA processivity etc.). Of course, the two scen- arios do not necessarily exclude each other and future challenges will certainly be aimed at clarifying these issues. For the moment, all these unresolved questions with regard to the role TDP-43 plays in disease have been extensively reviewed and discussed in several recent reports [22,51–55].
Still at the hypothetical
In general, disruption of SRSF1 and hnRNP A ⁄ B pro- teins is altered in various cancers, suggesting that defects at the autoregulatory level may contribute to the these pathologies [20,46]. On the other hand, importance of the TDP-43 protein for human disease was first described for its importance in the regulation of CFTR exon 9 skipping and the development of cystic fibrosis [47]. However, the major discovery that linked this protein with disease came in 2006 when it was found as a major neuropathological hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration [48].
level, however, there are several possibilities through which autoregulatory processes may influence pathological processes. First, the export of TDP-43 from the nucleus to the cyto- plasm and its sequestration in insoluble aggregates may well stimulate the autoregulatory system to attempt a major increase in the rate of TDP-43 pro- duction that would be needed to overcome any ‘loss- of-function’ effects in the nucleus. Such a process, however, even when successful may have some poten- tial drawbacks. First, the increase in energetic expen- diture to overcome the continuous loss of TDP-43 from the nucleus may well lead by itself to a certain degree of cell suffering if protracted over time. Sec- increased overall production of TDP-43 may ond,
In diseased neurons, the mostly nuclear TDP-43 is translocated in the cytoplasm where it aggregates and can also be aberrantly cleaved to generate C-terminal fragments, ubiquitinated, and phosphorylated at the C-terminal tail (Fig. 5). Regarding this issue, however, it should be noted that transient redistribution of TDP- 43 from the nucleus to the cytoplasm may be a natural response to injury following axonal ligation ⁄ axotomy [49,50]. At the moment, it is still unclear whether these changes trigger gain-of-function effects (due to the toxic fragments, aggregate formation or release of
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Fig. 5. Hypothetical disease implications of aberrant TDP-43 autoregulation pathways. This diagram shows how the disruption of TDP-43 autoregulatory processes by a variety of pathological alterations in the nuclear ⁄ cytoplasmic distribution of TDP-43 may contribute to disease.
aberrant
cellular damage. Furthermore, even the basic know- ledge of their existence should always be considered when interpreting the results of experimental approaches that are aimed at overrexpressing or underexpressing a particular protein. In fact, there is always the possibility that the expressed transgene might interfere uninten- tionally with these mechanisms, thus adding an addi- tional level of interpretation to experimental results.
the potential
also lead to an increase in aggregate formation or cleavage ⁄ phosphorylation within the cytoplasm, and thus to an increase in any eventual ‘gain-of-function’ effects that might occur as a conse- quence. With regard to these issues it is important to note that two studies have observed increased TDP- 43 mRNA levels in the brains of patients affected by various forms of frontotemporal lobar degeneration [56,57] and other studies have observed increased TDP-43 mRNA levels in several types of pathological samples [58,59]. Moreover, overexpression of TDP-43 in several animal models has consistently been dem- onstrated to be neuropathogenic in a dose-dependent manner [60].
In the other minireviews of this series, coordinated by Emanuele Buratti and Francisco Baralle [61], Rob- role played by ert Baloh discusses TDP-43 aggregation in disease [62] whilst Fabienne Fiesel and Philipp Kahle and Kathryn Volkening and Michael Strong further look at the roles played by TDP-43 and FUS ⁄ TLS on the general RNA metabo- lism and potential disease mechanisms [63,64].
Concluding remarks
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