Internal Ribosome Entry Site-Mediated Translation in Neuronal Protein Synthesis
Abstract and Keywords
While the majority of cellular mRNAs are translated by a cap-dependent mechanism, a subset of mRNAs can use an alternative mode of translation that, instead of cap, relies on discreet RNA elements that help to recruit the ribosome. This mode of translation, termed Internal Ribosome Entry Site (IRES)–dependent translation, is particularly important during conditions of compromised global protein synthesis or for a local, precisely timed translation of specific mRNAs. This latter purpose is of considerable importance in cells of the CNS for their normal function. Recently, the disruption of the IRES-mediated translation has also been linked to pathological processes, suggesting that full understanding and targeting of this peculiar mechanism could be used for therapeutic intervention.
Regulation of protein synthesis (translation) is a key cellular process that underpins cellular survival. Traditionally, the transcription and translation of the genome was considered a highly correlated phenomenon. This notion has been challenged by the demonstration that mRNA transcriptional outputs correlate with only about 40% of the total protein content in a cell (Schwanhausser et al., 2011; Tebaldi et al., 2012). This disconnect is further accentuated upon epidermal growth factor stimulation, for example, where up to 90% of transcripts exhibited uncoupled translation from transcription (Tebaldi et al., 2012). Interestingly, these studies also showed that highly expressed transcripts are sometimes poorly translated and, vice versa, poorly transcribed genes can be translated efficiently. This suggests that transcription and translation are largely independent of each other, further strengthening the notion that translational control has a major impact on regulating the proteome under certain conditions. It is therefore not surprising that many aberrant cellular processes require modification of the translation machinery and translation output (i.e., proteome). This is often the case in various stress responses and diseases. In addition, it is also particularly important in functioning of highly specialized cells, such as those of the central nervous system.
Neurons make hundreds if not thousands of synaptic connections that require independent maintenance and regulation. In addition, these synaptic connections have to specifically and appropriately respond to physiological stimuli that are unique to each synapse (reviewed in Iacoangeli & Tiedge, 2013). Localized translation is ideally suited to support this function, as it allows for precisely tailored, mosaic repertoire of proteins in individual dendrites and axons. In addition, localized and mRNA-specific translation can support experience-dependent and site-specific modulation of protein complement at each synapse, which is believed to be the basis for synaptic function, plasticity, and learning (for reviews see additional chapters in this volume).
General Control of Translation
Several recently written outstanding reviews describe in detail the key regulatory checkpoints of translation (e.g., Hershey, Sonenberg, & Mathews, 2012; Hinnebusch & Lorsch, 2012; Roux & Topisirovic, 2012). Therefore, only a summary is given here, with an emphasis on those translation factors and regulatory steps that intersect canonical and non-canonical modes of translation.
Translation begins with the recognition of mRNA by cellular translation apparatus and ends with the production of a protein. This entire process is for didactic purposes divided into four steps—initiation, elongation, termination, and ribosome recycling—but it is important to keep in mind that translation is a continuous process. All four steps are regulated; however, the majority of the control seems to center on the initiation step, which is thought to be rate limiting. This is probably because it is more effective to regulate (e.g., stop) the commencement of translation than to deal with unfinished, partly finished, or unwanted proteins that could arise at the wrong time or place and thus be detrimental to cells’ homeostasis, function, or survival.
The chief method of translation initiation occurs by means of the so-called cap-dependent scanning mode, which is the main source of de novo synthesized cellular proteins under normal growth conditions. Following synthesis in the nucleus, virtually all eukaryotic mRNAs are modified at both the 5′ and 3′ termini by addition of m7G cap and poly(A) tail, respectively. The purpose of these modifications is to protect the mRNA against degradation and to promote engagement of the mRNA by the translational apparatus. The recognition of mRNA by the translation apparatus occurs via the m7G cap and a specialized cap-binding protein, eIF4E (but see exceptions, to be discussed). In turn, eIF4E is bound by eIF4G (a scaffolding protein) and an RNA helicase eIF4A (this three-protein complex is termed eIF4F), and subsequently a cohort of additional initiation factors, including eIF3E, which recruit the small ribosomal submit to the 5′ end of the mRNA (Figure 1). It is believed that the mRNA-bound 43S ribosomal complex then repositions (scans) along the mRNA until the appropriate initiation codon (most often AUG) in the proper context is recognized and the polypeptide chain synthesis begins. It should be noted that the poly(A) tail and its associated poly(A)-binding protein PABP play a role of a translational enhancer, since the recruitment of 43S to the mRNA is greatly enhanced by eIF4G-PABP interaction (Hentze, Gebauer, & Preiss, 2007). This type of translation is referred to as cap-dependent, implying that the ability of translation machinery to recognize mRNA is absolutely dependent on the presence of m7G cap at the 5′ end of the mRNA.
In addition to this main mode of translation initiation, an existence of some other, alternative way(s) to initiate translation was also hypothesized, since it was observed that under conditions in which cap-dependent translation is severely compromised (e.g., viral infection or nutrient deprivation), a subset of mRNAs was shown to be still efficiently translated (e.g., Bushell et al., 2006; Johannes, Carter, Eisen, Brown, & Sarnow, 1999; Morley, Coldwell, & Clemens, 2005). In addition, it was observed that the proper cellular stress response (which is invariably accompanied by reduction in global protein synthesis) requires a reprograming of the cellular proteome, and this can be facilitated by the alternative initiation of translation (Spriggs, Bushell, & Willis, 2010; Spriggs, Stoneley, Bushell, & Willis, 2008). It was therefore proposed that selective translation that occurs by the alternative mode of translation initiation (most commonly by the Internal Ribosome Site Entry [IRES] mechanism) is a key mechanism that is required for cellular adaptation to stress and is used by cells to fine-tune their stress response (Holcik & Sonenberg, 2005; Holcik, Sonenberg, & Korneluk, 2000; Liwak, Faye, & Holcik, 2012; Ruggero, 2013; Silvera, Formenti, & Schneider, 2010).
Internal Ribosome Entry Site-Dependent Mode of Translation Initiation
Several cellular mRNAs are translated by a mechanism that does not appear to rely on the m7G cap and its associated factors. Cap-independent initiation of translation was first observed with RNA viruses (in particular from the picornaviridae family), whose RNA is naturally uncapped and yet efficiently translated by the host translation machinery (Pelletier & Sonenberg, 1988). These viruses also encode proteases that cleave several critical eukaryotic initiation factors to block translation of host proteins. For example, upon infection of cells with polio virus, the virus-encoded protease 2A cleaves eIF4G to inactivate the eIF4F cap-binding complex and consequently prevents the ribosome recruitment to capped mRNAs (K. A. Lee & Sonenberg, 1982). The consequences of this cleavage are twofold: (1) it prevents the synthesis of host proteins that might interfere with viral propagation (therefore functioning as a suppressor of innate immunity), and (2) it ensures that the host cell's translational machinery is now fully available for virus protein translation. This mechanism of alternative translation initiation was termed internal initiation (Pelletier & Sonenberg, 1988). Instead of cap, distinct functional RNA elements, termed IRES (Internal Ribosome Entry Site) elements, are found in the non-translated region of viral RNA and guide the recruitment of the 40S ribosome directly to or near the initiation codon (Figure 1). The primary sequence and secondary structures of these elements are very characteristic and are used to group similar IRES elements into distinct families of related elements. Importantly, the primary sequence and secondary structure also determines whether the IRES requires binding of additional protein(s) for its proper function. Thus, ribosomal recruitment can occur in the absence of any protein factors (as with dicistrovirus intergenic IRES, which binds directly to the 40S and 80S ribosomal subunits by mimicking the shape of tRNA (Kerr, Ma, Jang, Thompson, & Jan, 2016)), or with the aid of various combinations of canonical initiation factors (such as eIF3E, eIF5, and eIF5B) and auxiliary proteins (termed ITAFs—IRES Trans-Acting Factors; to be discussed) in case of other viral IRES, and as dictated by the IRES sequence and structure (for a comprehensive review of factor requirements on viral IRES see Jackson, 2013). These observations spurred study of cellular mRNAs to determine whether a similar mechanism(s) exists. Indeed, it was observed that a subset of cellular mRNAs (up to 10%) was efficiently translated in cells infected with poliovirus (which inhibits cap-dependent translation; Johannes et al., 1999). Subsequent studies described functional IRES elements in a variety of cellular mRNAs. Interestingly, many of these mRNAs encode proteins involved in processes such as cell proliferation and apoptosis, and are critical in determining the survival of a cell under physiological and pathophysiological stress conditions (Holcik & Sonenberg, 2005). This is, perhaps, not surprising, given that these cellular processes require strict control of gene expression. IRES-mediated translation thus provides a means for escaping the global decline in protein synthesis and allows the selective translation of specific mRNAs that are required under given condition. Thus, we and others have proposed that the selective regulation of IRES-mediated translation is important for the regulation of cell death and survival (Holcik & Sonenberg, 2005; Holcik, Sonenberg, et al., 2000; Lewis & Holcik, 2005; Sachs, Sarnow, & Hentze, 1997; Silvera et al., 2010). Indeed, the experimental data from many laboratories have now validated this hypothesis in many models (reviewed in Elroy-Stein & Merrick, 2007; Silvera et al., 2010). The in vivo evidence supporting this concept is particularly striking. For example, the selective impairment of IRES-mediated translation but not cap-dependent translation results in enhanced apoptosis of hematopoietic progenitors and stem cells, leading to the fatal progressive bone marrow failure syndrome known as dyskeratosis congenita and its associated tumorigenesis (Bellodi, Kopmar, & Ruggero, 2010; Bellodi, Krasnykh, et al., 2010; Yoon et al., 2006). A switch to IRES-dependent translation has been implicated in breast cancer growth and angiogenic potential in vivo (Braunstein et al., 2007) and in the acquired resistance of cancer cells to radiation-induced apoptosis (Gu et al., 2009). Similarly, HPV-induced transformation of human keratinocytes is accompanied by a switch from cap-dependent to IRES-dependent translation (Mizrachy-Schwartz, Kravchenko-Balasha, Ben-Bassat, Klein, & Levitzki, 2007).
It needs to be stressed, however, that several of the cellular IRESs were subsequently shown to be artefacts of poorly controlled experiments. Many, if not most of the early studies to describe and characterize cellular IRES relied almost exclusively on a use of artificial bi-cistronic DNA constructs. In these constructs, the cap-dependent translation is monitored through the expression of the 5′ cistron, which is followed by a short linker preceding the second cistron. The suspected IRES is then inserted into the linker region of the bi-cistronic construct and translation of the second cistron is taken to indicate IRES activity. However, translation of the second cistron could also be a result of a cryptic promoter within the suspected IRES (giving rise to an independent, capped mRNA transcript harboring a second cistron), or alternative splicing (that would result in excision of the first cistron; Holcik et al., 2005). While utilization of stringent controls such as RNA transfections (to eliminate cryptic promoter activity), qRT-PCR, Northern blots, or siRNAs targeting specific cistrons (to monitor integrity of the mRNA) can discern between these alternate explanation, not all published experiments were carefully designed (Jackson, 2013). Justifiably, this resulted in questioning of the validity of cellular IRES mechanism in general and is still a hotly debated topic (Jackson, 2013; Komar, Mazumder, & Merrick, 2012). Nevertheless, rigorous experiments, both in vitro and in vivo, confirmed several cellular IRESs to be bona fide regulatory elements that during cellular stress drive translation of their respective proteins in a manner that seems independent of eIF4E and/or cap. Further evidence for the existence of this mechanism is now emerging from large, genome-wide studies. For example, a recent high-throughput bicistronic assay identified hundreds of novel IRES elements in the human transcriptome (Weingarten-Gabbay et al., 2016). Subsequent characterization of these elements confirmed some previously identified elements (such as secondary structure, short sequence motifs, and base pairing with 18S rRNA; Baird, Turcotte, Korneluk, & Holcik, 2006), but also added new potential mechanisms (IRES within the 3′UTR) of how cellular IRESs operate (Weingarten-Gabbay et al., 2016; Weingarten-Gabbay & Segal, 2016).
Unlike viral IRES, the mechanism of cellular IRESs is still poorly understood. Complicating the issue is the fact that cellular IRESs do not share sequence of structure similarities (Baird, Lewis, Turcotte, & Holcik, 2007; Baird et al., 2006) and they function in a different manner from most viral IRESs. That is, most cellular IRES elements require binding of some of the canonical initiation factors, as well as auxiliary ITAFs that modulate the IRES activity (Holcik & Sonenberg, 2005). Most of the ITAFs identified thus far are RNA-binding proteins that fulfill a variety of functions, including involvement in mRNA splicing, export, and stress granule formation, as well as important roles in cap-dependent translation initiation (Komar & Hatzoglou, 2011). The binding of ITAFs can either enhance or repress IRES activity; it is thought that the positive regulators act either as RNA chaperons that aid in the formation of the proper IRES structure (e.g., Mitchell, Spriggs, Coldwell, Jackson, & Willis, 2003) or by directly recruiting the ribosome to the mRNA (e.g., Thakor et al., 2017). The precise mechanism of how the repressive ITAFs function is not clear, however. Interestingly, many ITAFs shuttle between the nucleus and cytoplasm, and this shuttling is regulated by posttranslational modifications such as phosphorylation in response to a variety of triggers (e.g., Courteau et al., 2015). Therefore, the cytoplasmic availability of positive or negative regulators can also determine the strength of IRES translation (Cammas, Lewis, Vagner, & Holcik, 2008).
IRES Translation in CNS
Although the IRES-dependent translation initiation has been characterized most thoroughly in the context of cellular stress response, and in particular during tumorigenesis and cancer formation, recent data strongly suggest that it plays a critical role in the function of CNS, both under physiological but also pathological conditions. The first observation of IRES-dependent translation was made in dendrites. Because the concentration of components of the translation apparatus is thought to be low in dendrites, Pinkstaff et al. searched for alternative means of translation of dendritically localized mRNAs (Pinkstaff, Chappell, Mauro, Edelman, & Krushel, 2001). They identified five mRNAs whose 5′ UTRs support IRES-dependent translation and are less sensitive to the inhibition of eIF4E. These mRNAs encode for activity regulated cytoskeletal protein (ARC), the α subunit of calcium-calmodulin-dependent kinase II (αCaM Kinase II), dendrin, the microtubule-associated protein 2 (MAP2), and neurogranin (RC3). In addition to supporting translation in bi-cistronic constructs in established cell lines, the authors further demonstrated the ability of RC3 IRES to support translation in dendrites of primary hippocampal neurons. Notably, the IRES-dependent translation was relatively more efficient in the dendrite than in the cell body, suggesting that this mechanism might be responsible for the synthesis of proteins required for the strengthening of active synapse (Pinkstaff et al., 2001).
The physiological role of IRES-mediated translation in neurons was demonstrated in sensory neurons of sea slug Aplysia californica. Induction of ovulation and egg-laying behavior in Aplysia is triggered by an egg-laying hormone (ELH) that is produced by bag cell neurons (W. Lee & Wayne, 1998). Early observations determined that the electrical afterdischarge (AD), which leads to depletion of ELH, also rapidly stimulates rate of translation of ELH from an existing, stable ELH mRNA (W. Lee & Wayne, 1998). This increase in ELH translation is mediated by an IRES within the 5′ UTR of the ELH mRNA whose activity is stimulated by AD (Dyer et al., 2003). Importantly, the AD leads to dephosphorylation of eIF4E, which is thought to attenuate cap-dependent translation. A similar mechanism has been described during mitosis in which the decreased phosphorylation of eIF4E correlates with induction of IRES-mediated translation (Pyronnet, Dostie, & Sonenberg, 2001). Indeed, forced dephosphorylation of eIF4E in bag cell neurons was sufficient to cause the switch to IRES-dependent translation (Dyer et al., 2003).
Neurotrophin receptors affect multiple cellular functions, in particular during the development and maintenance of the nervous system (Huang & Reichardt, 2003). TrkB is one member of this family of receptors. TrkB is activated by BDNF and promotes local protein synthesis, glutamate receptor phosphorylation, synaptic efficacy, and enhanced cell survival (Dobson, Minic, Nielsen, Amiott, & Krushel, 2005). Although TrkB expression is regulated at the level of transcription, mRNA stability, and protein half-life, regulation at the level of protein synthesis would be expected in neurons, in particular since TrkB mRNA is transported to dendrites for local translation (Righi, Tongiorgi, & Cattaneo, 2000). The 5′ UTR of human TrkB mRNA was thus examined for its ability to selectively control translation of TrkB. It was found that it harbors an IRES that supports translation of a reporter mRNA in neuronal cells even when cap-dependent translation is inhibited by overexpression of 4E-BP (Dobson et al., 2005). A similar situation was observed with mouse TrkB, which was shown to contain two distinct IRES elements in two alternatively transcribed mRNA that, however, encode the same TrkB open reading frame (Timmerman, Pfingsten, Kieft, & Krushel, 2007). These two IRES are controlled differently, based on the differentiation state of the SH-SY5Y neuronal cell line used; while the IRES found in exon 1 is constitutively active, the exon 2 IRES is active only in retinoic acid differentiated SH-SY5Y cells. Mechanistically, this could be accomplished through an RNA binding protein PTB. Although PTB binds both exon 1 and exon2 IRESs, only exon 2 IRES requires PTB for its activity (Timmerman et al., 2007). Although neither study examined the translation of the endogenous TrkB, it has been noted that in the young rat brains the TrkB mRNA is synthesized during ischemic injury and activation of the TrkB receptor promotes cell survival (Narumiya, Ohno, Tanaka, Yamano, & Shimada, 1998). Since in other model systems the IRES-dependent translation has been linked to enhanced cell survival (Holcik & Sonenberg, 2005), these observations suggest that it might be the IRES-dependent translation mechanism that mediates enhance expression of TrkB under these conditions.
Fibroblast growth factor 2 (FGF-2) is one of the key growth factors that shapes both embryonal and adult CNS development (Woodbury & Ikezu, 2014). Owing to its crucial developmental role, FGF-2 expression is regulated both spatially and temporally, coinciding with development of specific brain regions (Woodbury & Ikezu, 2014). In particular, the FGF-2 mRNA generates five protein isoforms through the use of multiple alternative translation initiation sites (Arnaud et al., 1999; Florkiewicz & Sommer, 1989) and an IRES (Vagner et al., 1995). The activity of the FGF-2 IRES was measured using a transgenic reporter mouse and was shown to mimic expression of the endogenous FGF-2, with particularly high expression in the brain (Creancier, Morello, Mercier, & Prats, 2000). Further dissection of the FGF-2 IRES activity pattern showed strict spatiotemporal regulation during embryogenesis and into adulthood with marked peak in postnatal day 7, which is coincidental with neuronal maturation, and it was particularly enriched in synaptoneurosomes (Audigier et al., 2008). In isolated cortical neurons the FGF-2 IRES activity was stimulated by co-culturing neurons with astrocytes, and this could be recapitulated by using astrocyte-conditioned medium, suggesting a release of stimulatory diffusible factor from astrocytes (Audigier et al., 2008). Interestingly, FGF-2 itself was identified as one such stimulatory factor (Audigier et al., 2008). In addition, blockage of spontaneous electrical activity in cultured neurons by tetrodotoxin attenuated FGF-2 IRES activity, suggesting that spontaneous electrical activity contributes to the regulation of FGF-2 IRES during development (Audigier et al., 2008).
IRES Translation Is Linked to Neurodegenerative Disease
Expression of the amyloid precursor protein (APP) is a critical factor in the development of Alzheimer’s disease since it serves as a precursor of β-amyloid peptide in the brain (Farlow, 1998). While investigating the translation of mRNAs during the global translational repression through mitosis Qin and Sarnow noted that APP mRNA remained associated with actively translating ribosome in mitotically arrested HeLa cells (Qin & Sarnow, 2004). Subcloning of the APP 5′ UTR into a bi-cistronic DNA vector confirmed the presence of an IRES element. Subsequent work from the Krushel group confirmed the IRES-mediated translation of APP in neuronal cells and further elucidated the mechanisms controlling translation of APP (Beaudoin, Poirel, & Krushel, 2008). Expression of APP increased in rat neural C6 or human SH-SY5Y neuroblastoma cells in which cap-dependent translation was inhibited with an mTOR inhibitor rapamycin, or in cells in which eIF4E has been depleted by an siRNA. The validity of a bona fide IRES was confirmed using DNA and RNA constructs both in cells and in vitro. Most importantly, however, this paper connected the IRES mechanism of APP translation to physiologically relevant conditions. The evidence from postmortem brains from individuals with Alzheimer’s disease linked two conditions—increased intracellular iron concentration and acute ischemic injury—with the presence of β-amyloid peptide plaques in the brain (Connor, Menzies, St Martin, & Mufson, 1992; Richardson, 2004). Simulation of these conditions in C6 or SH-SY5Y cells led to an increase in APP mRNA translation as well as APP IRES activity (Beaudoin et al., 2008). This work suggests that IRES-dependent translation of APP is critical for APP expression. Although the role of this mechanism in normal, physiological conditions of the brain is unclear, it suggests that specific targeting of this mechanism could be exploited therapeutically in Alzheimer’s disease.
Another characteristic of the Alzheimer’s disease is the occurrence of neurofibrillary tangles of hyperphosphorylated protein tau (Harada et al., 1994). Using a variety of stringent methods the 5′ UTR of tau mRNA was shown to harbor an IRES element that was active in human neuroblastoma cell line SK-N-SH or in vitro (Veo & Krushel, 2009). In addition, in cells with siRNA-mediated knock-down of eIF4E the synthesis of endogenous tau protein increased, providing further support for the importance of IRES in the translation of tau. Further biochemical analysis and sequence mapping of the tau IRES disclosed extensive secondary structure and domain architecture that were more similar to viral than to cellular IRESs (Veo & Krushel, 2012). Interestingly, two naturally occurring single nucleotide polymorphisms (SNP) within the tau IRES that are linked to the development of Parkinson disease resulted in a complete loss of IRES activity (Veo & Krushel, 2012). This observation is both intriguing and puzzling; the formation of neurofibrillary tangles has been seen in patients with Parkinson disease (Arima et al., 1999), yet the Parkinson disease-associated SNPs in tau 5′ UTR suppresses tau IRES activity, which should lead to decreased tau expression and diminish tangles. Since the effect of these SNPs on the expression of endogenous tau have not been examined it is possible that the tau IRES behaves differently when found in the context of the endogenous mRNA.
A pathological signature of Parkinson disease are fibrillar aggregates known as Lewy bodies. Although Lewy bodies contain over 70 different molecules, the predominant constituent is α-synuclein, SNCA (Wakabayashi, Tanji, Mori, & Takahashi, 2007). The 5′ UTR of human SNCA mRNA was examined for bearing translation regulatory elements and was shown to substantially enhance translation of a reporter construct and to exhibit IRES-activity in both the DNA and RNA-based reporter systems (Koukouraki & Doxakis, 2016). Rapamycin, an mTOR inhibitor, can be used to block cap-dependent translation by activating eIF4E inhibiting proteins, 4E-BPs (Beretta, Gingras, Svitkin, Hall, & Sonenberg, 1996) while the IRES-dependent translation remains mainly undisturbed (Shi, Sharma, Wu, Lichtenstein, & Gera, 2005). Interestingly, the 5′ UTR of SNCA could support rapamycin-independent translation in Neuro-2a cells. Furthermore, translation of the endogenous α-synuclein was observed in rapamycin treated HEK-293 cells, suggesting the use of an IRES. Since SNCA expression is deregulated in Parkinson disease the authors also tested if various stress inducers, particularly those associated with ageing brain, alter the activity of SNCA IRES. Indeed, depolarization with KCl, iron accumulation, serum deprivation and oxidative stress all induced both the SNCA IRES activity as well as endogenous SNCA protein levels, indicating that SNCA IRES contributes to accumulation of SNCA under stress conditions (Koukouraki & Doxakis, 2016). Targeting SNCA IRES could therefore represent additional strategy to combat α-synuclein toxicity.
BiP, also known as GRP78, is a molecular chaperone involved in the resolution of the unfolded protein response activated by an endoplasmic reticulum stress in the cells (Casas, 2017). BiP is gaining interest in the field of neurodegeneration since many, if not all age-related neurodegenerative disorders are commonly associated with the accumulation of misfolded or aggregated proteins. Indeed, the levels of BiP are altered in brains of Alzheimer’s and Parkinson’s disease patients and, conversely, are decreased during aging (Casas, 2017). The expression of BiP was shown to increase during ischemic preconditioning and regeneration, while decrease during neurodegenerative processes (Penas, Casas, Robert, Fores, & Navarro, 2009; Penas et al., 2011; Zhang et al., 2015). In addition, a mutation in BiP disrupts proper development of the thalamocortical exon projections and other forebrain axon tracks (Favero et al., 2013).
BiP function is controlled primarily at the level of its interaction with and dissociation from the ER membrane-anchored sensor proteins PERK, IRE1 and ATF6. In addition, BiP expression is regulated at the level of translation initiation by an IRES, in particular in response to cellular stress (Johannes & Sarnow, 1998; Kim & Jang, 2002; Macejak & Sarnow, 1991). Although the BiP IRES and its interacting proteins were characterized before (Johannes & Sarnow, 1998; Kim, Back, Rho, Lee, & Jang, 2001; Kim, Hahm, & Jang, 2000; Kim & Jang, 2002; Macejak & Sarnow, 1991; Thoma, Bergamini, Galy, Hundsdoerfer, & Hentze, 2004), it was shown only recently that BiP IRES is active in sensory axons (Pacheco & Twiss, 2012). Using axonally targeted fluorescent bicistronic reporter Pacheco and Twiss detected robust rat BiP IRES activity in both the cell body and axons in cultured rat DRG neurons. The axonal activity occurred even after photobleaching and was sensitive to inhibitors of translation, suggesting that the adult rodent sensory neurons have the capacity to support BiP IRES-mediated translation (Pacheco & Twiss, 2012). Although this study did not examine translation of the endogenous BiP in axons, it was shown previously that BiP mRNA is transported to and subsequently locally translated in sensory axons (Willis et al., 2005).
Stimulation of IRES Translation by Opioids
Opioids, such as morphine, signal through specific receptors that are expressed primarily in the central nervous system (Tao & Auerbach, 2002). The mu-opioid receptor (MOR) is the key mediator of the analgesic effect and its expression is regulated by both transcriptional and posttranscriptional mechanisms (P. T. Lee et al., 2014; Song, Choi, Law, Wei, & Loh, 2017). One of the proteins that activates transcription of MOR in neuronal cells is an RNA binding protein hnRNP K (Choi et al., 2008). Notably, injection of morphine into mice elicited robust neuron-specific increase in hnRNP K protein levels, and similar increases were seen in rat primary cortical neurons, or in HEK 293 cells expressing MOR that were treated with morphine (P. T. Lee et al., 2014). Further dissection of the mechanism responsible for morphine-mediated induction of hnRNP K identified an IRES element in the 5′ UTR of hnRNP K mRNA whose activity can be enhanced by morphine (P. T. Lee et al., 2014). In addition, morphine treatment results in a cytoplasmic accumulation of hnRNP K. It has been described for several ITAFs, most notably hnRNP A1, that cytoplasmic accumulation of these proteins (in particular during cellular stress conditions) is needed for their ITAF activity (Cammas et al., 2008). Interestingly, hnRNP K was shown to interact with its own 5′ UTR and act as an ITAF, and this interaction is enhanced by morphine, suggesting an existence of a positive feedback loop: morphine treatment results in enhanced translation of hnRNP K which in turn drives both the transcription of MOR receptor (nuclear hnRNP K) as well as strengthening hnRNP K interaction with its own IRES (cytoplasmic hnRNP K), thus increasing expression levels of hnRNP K. In mice, opioid receptor activation is required for hnRNP K expression since the treatment of animals with naloxone, an opioid antagonist prior to morphine injection prevented the morphine-dependent stimulation of hnRNP K expression (P. T. Lee et al., 2014). Finally, siRNA-mediated reduction of hnRNP K in mice produced approximately 30% inhibition of basal nociceptive sensitivity (measured by tail-flick latency) and significantly attenuated morphine-mediated analgesic effect (P. T. Lee et al., 2014). These data thus provide a first mechanistic glimpse of the translational control of opioid-based pain control.
IRES Control of Neuronal Apoptosis
IRES-dependent mechanism of translation initiation is particularly well suited to maintain or enhance expression of survival proteins under conditions of cellular stress (Holcik & Sonenberg, 2005). This has been nicely demonstrated, both in vitro and in vivo for a number of pro-survival proteins, particularly in the context of tumorigenesis (Bellodi, Kopmar, et al., 2010; Bellodi, Krasnykh, et al., 2010; Braunstein et al., 2007; Faye et al., 2015; Gu et al., 2009; Yoon et al., 2006). One such anti-apoptotic protein is XIAP, the prototypical member of the Inhibitor of Apoptosis (IAP) protein family. The IAP proteins are critical regulators of apoptosis; a subset of IAPs binds to and inhibits key caspases involved both in the initiation and the execution steps (Holcik & Korneluk, 2001; Salvesen & Duckett, 2002). Cellular levels of XIAP protein are regulated by several mechanisms including protein degradation and changes in the protein synthesis. However, a mechanism that predominates during cellular stress is the selective XIAP translation via an IRES element (Bevilacqua et al., 2010; Durie et al., 2011; Gu et al., 2009; Holcik, Lefebvre, Yeh, Chow, & Korneluk, 1999; Holcik, Yeh, Korneluk, & Chow, 2000; Lewis et al., 2007; Muaddi et al., 2010; Nevins, Harder, Korneluk, & Holcik, 2003; Riley, Jordan, & Holcik, 2010; Yamagiwa, Marienfeld, Meng, Holcik, & Patel, 2004). XIAP is encoded by two mRNAs with distinct 5′ UTRs; the major, shorter 5′ UTR promotes a basal level of XIAP expression under normal growth conditions, while the less abundant, longer 5′UTR contains an IRES and supports cap-independent translation during stress (Riley et al., 2010). Importantly, the IRES-driven upregulation of XIAP in response to irradiation, serum deprivation, glucose deficiency, IL-6 treatment or cellular transformation as well as various other experimental settings, in situation when normal cap-dependent translation fails, has been shown to enhance cell survival, suggesting a central role for IRES-dependent translation of XIAP in mediating cellular fate, both in cells and in vivo (Aird et al., 2008; Aird, Ghanayem, Peplinski, Lyerly, & Devi, 2010; Blais et al., 2006; Durie et al., 2011; Gu et al., 2009; Holcik, Yeh, et al., 2000; Mizrachy-Schwartz et al., 2007; Muaddi et al., 2010; Nevins et al., 2003; Riley et al., 2010; Thakor & Holcik, 2012; Ungureanu et al., 2006; Warnakulasuriyarachchi, Cerquozzi, Cheung, & Holcik, 2004; Yamagiwa et al., 2004; Yoon et al., 2006). Clearly, in these cases, and we suspect more generally, the role IRES-mediated translation plays for the inhibition of apoptosis is biologically important. In fact, specific targeting of XIAP IRES translation was recently used to develop cancer therapeutics (Gu et al., 2016).
Cerebral ischemic injury activates apoptotic cell death in neurons, and is accompanied by a transient increase in XIAP levels in rescued cells in rats and mice (Siegelin, Kossatz, Winckler, & Rami, 2005; Spahn, Blondeau, Heurteaux, Dehghani, & Rami, 2008). Similarly, hippocampal HT22 cells treated with staurosporine exhibit an increase in XIAP expression (Spahn et al., 2008). In both models of neuronal cell death the expression of the RNA binding protein hnRNP C1 has been observed to coincide with XIAP expression (Spahn et al., 2008). Although direct evidence for the regulation of XIAP by hnRNP C1 during ischemic injury is not available, previous work has identified hnRNP C1 as one of the ITAFs that enhances IRES-dependent translation of the XIAP IRES (Holcik, Gordon, & Korneluk, 2003) suggesting that IRES-mediated control of XIAP contributes to the regulation of neuronal apoptosis.
N-myc is an oncogenic transcription factor of the myc family that is expressed primarily in neuronal tissues during early development. Similarly to other orthologs of the Myc family of proteins, misregulated expression of N-myc is linked to cancer, in particular neuroblastoma (Ruiz-Perez, Henley, & Arsenian-Henriksson, 2017). N-myc is essential for the proper fetal development as N-myc null mice die between 10.5 and 12.5 days of gestation with significant defects in organ development, most notably heart and the cranial and spinal ganglia. In the context of neuroblastomas, N-myc has been shown to have a dual role in the regulation of apoptosis—it is involved in the upregulation of pro-apoptotic phorbol-12-myristate-13-acetate-induced protein 1 (NOXA) and it sensitizes cells to cytotoxic drugs (Ham et al., 2016). On the other hand, through the regulation of p53 and H-Twist N-myc can increase apoptotic resistance as well (Valsesia-Wittmann et al., 2004; Yogev et al., 2016).
All members of the Myc family contain an IRES in their mRNA (Cobbold et al., 2008). However, these IRESs exhibit distinct patterns of expression and canonical factors requirement (Cobbold et al., 2008; Jopling & Willis, 2001; Spriggs et al., 2009). Notably, the N-myc IRES activity decreases during neuronal differentiation (Jopling & Willis, 2001) thus recapitulating, at least partially, decreasing expression of endogenous N-myc during development (Ruiz-Perez et al., 2017). In addition, the N-myc IRES has a lower requirement for the ternary complex (Spriggs et al., 2009), and would therefore be expected to operate efficiently under conditions of increased eIF2α phosphorylation, such as during hypoxia. Although the N-myc IRES requires eIF3 for its function, the mode of recruitment of eIF3 to the N-myc IRES appears to be independent of eIF4F (Spriggs et al., 2009). Such recruitment mode has been described for the XIAP IRES, in which eIF3 binds directly to the XIAP IRES RNA in a structure-dependent manner, followed by recruitment of PABP and the 40S ribosome (Thakor et al., 2017). Whether the N-myc IRES recruits eIF3 in the same way remains to be shown.
IRES-mediated translation has evolved to allow cells to fine-tune their proteome under various conditions. It is also emerging as a critical mechanism that allows for localized and precisely timed expression of distinct proteins in cellular extensions, and in response to environmental cues (Figure 1). We are only beginning to understand the full extent by which IRES translation shapes the function of CNS, and by extension how dysregulated IRES translation (or mutations in key parts of the IRES system) contributes to disease. Nevertheless, several small molecule inhibitors of IRES-mediated translations were reported in recent years (Berry et al., 2011; Didiot et al., 2013; Vaklavas et al., 2015; Venkatesan & Dasgupta, 2001; Zhou, Rynearson, Ding, Brunn, & Hermann, 2013). Although none of these approaches specifically looked for inhibitors of neuronal IRES (such as APP or SNCA) they established a methodology framework that could be extended to those mRNAs that utilize IRES translation specifically in CNS.
Despite a considerable progress in elucidating the role of IRES-dependent translation in the function of CNS, there remain many unanswered questions. For example, are there multiple mechanisms of alternative translation initiation that are used preferentially in response to various cues? Is the IRES mediated translation used to coordinate expression of distinct cohorts of mRNAs to allow for neuronal plasticity? Are there genetic links between diseases of CNS and translation machinery players? And could these be specifically targeted for the development of therapies?
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