Internal Ribosome Entry Site (IRES)-Mediated Translation and Its Potential for Novel mRNA-Based Therapy Development
Abstract
:1. Introduction
2. Cap- Versus IRES-Dependent Translation Initiation
2.1. Canonical 5′ Cap-Dependent Translation Initiation
2.2. IRES-Dependent Translation Initiation and Its Regulation by IRES Trans-Acting Factors
2.2.1. IRES-Dependent Translation of Circular RNAs (circRNA)
2.2.2. IRES-Mediated Translation of Different Protein Isoforms from Monocistronic Genes
2.2.3. IRES-Mediated Translation of Polycistronic Genes
- (i)
- a single transcript that coordinately expresses at least two protein subunits that are part of a multi-subunit complex. This is the case of tenocyclidine [1-(1-(2-thienyl)cyclohexyl)piperidine binding protein (TCP-BP), which is present in rat brain synaptic membranes and binds glutamate agonists. It is composed of two subunits, PRO-1 and PRO-2; the former is cap-dependently translated, whereas the latter is IRES-dependently translated through an element occurring in the intercistronic region [43,51];
- (ii)
- a single transcript that encodes different protein products with similar structure and function that are differentially expressed, i.e., transcripts that include two cistrons, one encoding a primary protein expressed through a cap-dependent translation mechanism and another encoding a secondary protein translated through a cap-independent mechanism. An example of such a transcript is the free fatty acid receptor 1 (FFAR1), which encodes the G-protein receptor (GPR) 40 and the GPR41 [52]. GPR40 is a receptor for long chain fatty acids, whereas GPR41 is activated by short chain fatty acids [43,53]. This cistronic organisation accounts for coordinated regulation of both receptors. Another example that fits in this group is the meloe mRNA. This is a polycistronic transcript responsible for expressing the melanoma antigens MELOE-1 and MELOE-2, which contain functional IRESs to mediate the expression of such proteins [54]. IRES-mediated translation accounts for the selective expression of these two proteins in melanoma cells, rather than in normal melanocytes [54]. Charpentier et al. identified MELOE-3, a protein with poor immunogenicity encoded by an additional ORF in the 5′ UTR of meloe and translated by the cap-dependent mechanism, reinforcing the importance of targeting MELOE-1 and MELOE-2 IRES-dependent translation for melanoma immunotherapy [43,55];
- (iii)
- a single transcript that encodes functionally distinct proteins whose expression is programmatically related, meaning two proteins that function differentially but play a role in the same pathway [43], like the PITSLRE/CDK11 duplicate genes CdcL1 and CdcL2. Each one encodes two cyclin-dependent protein kinase isoforms, p110 and p58, of which the p58 is IRES-translated [56]. This IRES-dependent translation is cell cycle-dependent and allows translation of p58 during the G2/M transition [43,56]. Also, the voltage-gated Ca2+ channel (CACNA1A) mRNA is bicistronic and encodes both the normal-length α1A subunit (wild-type transcription factor α1 antichymotrypsin, α1ACT) and the expanded polyQ tract subunit (extended α1ACT). The latter is an IRES-translated protein from at least one spliced form of the same CACNA1A mRNA [57]. The myotrophin (MTPN) gene is also transcribed into an mRNA with two adjacent tandem ORFs. These ORFs express two proteins—myotrophin, translated through the cap-dependent mechanism, and autosomal dominant adult-onset distal myopathy-6 (MPD6), translated through an IRES element [58]. Similar to what happens to CACNA1A, the proteins encoded by MTPN have distinct roles, but are programmatically related [43]—myotrophin works in the dimerization of NFκB in cardiac tissue and MPD6 is associated with the immune response in some types of cancer [58];
- (iv)
- a single transcript that encodes proteins produced by stimulus-coupled protease cleavage or by IRES-dependent translation initiation [43]. This is the case of transcripts with two overlapping ORFs that code products required for signal transduction, in which the first cistron codes for a receptor initiating signal transduction upon ligand binding, whereas the downstream cistron produces a constitutively active signal [43]. Notch2, for instance, is a gene encoding a receptor involved in the ligand-receptor notch-signalling pathway [59]. The interaction of Notch2 with the extracellular notch ligand triggers the protease cleavage of the C-terminal polypeptide, the notch intracellular domain (NICD) [60]. Notch2-ICD is translated via an IRES occurring in the Notch2 coding region [60]. Another example is the Her2 gene, a tyrosine kinase receptor involved in cancers and neurodegenerative diseases. It is a polycistronic gene encoding the full-length HER2 protein and several C-terminal fragments (CTF) [61]. These CTFs are translated through IRESs within the HER2 coding region [43,61];
- (v)
- a single transcript with different ORFs separated by IRES-containing intercistronic regions. This is the case of the tricistronic c-myc mRNA that, when transcribed from the alternative upstream promoter P0, contains three different ORFs separated by two intercistronic regions each containing an IRES [62,63]. The two identified IRESs mediate the translation of both the second and third ORFs that encode the MYCHEX1 and c-myc1/c-myc2 proteins, respectively [63].
3. IRES-Dependent Translation Dysregulation-Related Diseases
3.1. Neurodegenerative Diseases
3.1.1. Spinocerebellar Ataxia Type 6 (SCA6)
3.1.2. Fragile X Syndrome
3.1.3. Alzheimer’s Disease
3.1.4. Parkinson’s Disease
3.1.5. Amyotrophic Lateral Sclerosis and Other Neurological Conditions
3.2. Muscular Atrophies
3.2.1. Ischemic Cardiomyopathy (Lymphangiogenesis Regulation)
3.2.2. Myogenesis Regulation
3.2.3. Duchenne Muscular Dystrophy
3.3. Other Specific Diseases
3.3.1. Diamond-Blackfan Anaemia
3.3.2. Diabetes
4. RNA-Based Therapies to Modulate Translation Initiation Dysregulation
4.1. IRESs as Targets
4.2. IRESs as Tools
4.2.1. Parkinson’s Disease
4.2.2. Diabetes
4.2.3. Fabry Disease
4.2.4. Mocupolysaccharidosis III A
4.2.5. Autoimmune Diseases
4.2.6. Cardiovascular Diseases
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Pathologies | IRES-Containing Transcripts | Related ITAFs | Tested RNA-Based Therapies | References | |
---|---|---|---|---|---|
Neurodegenerative diseases | Spinocerebellar ataxia type 6 | CACNA1A | n.i. * | miRNA-based therapy | [65,66] |
Fragile X syndrome | fmr1 | hnRNPQ | n.i. * | [70] | |
Alzheimer’s disease | p53 (p44 isoform) | APP (AICD), nucleolin | n.i. * | [74] | |
Parkinson’s disease | HIF-1α | PINK1 | Antisense oligo nucleotide reducing the expression of α-synuclein pathogenic protein | [82,83] | |
Amyotrophic lateral sclerosis | Related RBPs: hnRNPA2/B1, hnRNPA1, FUS | n.i. * | [84] | ||
Muscular atrophies | Ischemic cardiomyopathy | VEGFA, VEGFC, FGF1 | hnRNPL, VASH1 | n.i. * | [90,91] |
Myogenesis regulation | FGF1/FGF2 | hnRNPM, p54nrb | n.i. * | [95,110] | |
Duchenne muscular dystrophy | utrophin A | eEF1A2 | IRES over-expression by small molecules | [102,111] | |
Other diseases | Diamond-Blackfan anaemia | Bag1/Csde1, p53 | Rps19, Rpl11 | n.i. * | [107] |
Diabetes | INR/IGF-1R | PTBP1, HuR, hnRNPC | miRNA-based therapy | [108,109] |
Disease/Condition | IRES Gene Therapy | Expressed Proteins | Purpose | References |
---|---|---|---|---|
Parkinson’s disease |
|
|
| [147,148,149,150] |
Diabetes | Multicistronic adenoviral construct | Pancreatic and duodenal homeobox-1 (Pdx1), Neurogenin 3 (Ngn3) V-musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) | Reprogramming of hepatocytes into insulin-producing cells in vitro and correcting the diabetic state in vivo | [151] |
Fabry disease | Bicistronic retroviral vectors | a-Gal A gene drug-selectable multidrug resistance gene 1 (MDR1) | Restore the deficiency of the α-galactosidase A (a-Gal A) enzyme | [152] |
Mucopoly- saccharidosis IIIA | Adeno-associated virus (AAV)-based bicistronic vector | Heparan-N-sulfamidase and N-sulfoglycosamine sulfohydrolase (SGSH) Sulfatase-modifying factor (SUMF1) | Improve heparan sulfate catabolism and decrease microglial activation | [153] |
Autoimmune diseases | Bicistronic lentiviral vector | Two IL-27 subunits (p28 and EBI3) | Promote the differentiation of T-cells that secrete IL-10 | [154] |
Cardiovascular diseases |
|
|
| [155,156,157,158] |
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Marques, R.; Lacerda, R.; Romão, L. Internal Ribosome Entry Site (IRES)-Mediated Translation and Its Potential for Novel mRNA-Based Therapy Development. Biomedicines 2022, 10, 1865. https://doi.org/10.3390/biomedicines10081865
Marques R, Lacerda R, Romão L. Internal Ribosome Entry Site (IRES)-Mediated Translation and Its Potential for Novel mRNA-Based Therapy Development. Biomedicines. 2022; 10(8):1865. https://doi.org/10.3390/biomedicines10081865
Chicago/Turabian StyleMarques, Rita, Rafaela Lacerda, and Luísa Romão. 2022. "Internal Ribosome Entry Site (IRES)-Mediated Translation and Its Potential for Novel mRNA-Based Therapy Development" Biomedicines 10, no. 8: 1865. https://doi.org/10.3390/biomedicines10081865