Internal Ribosome Entry Site (IRES)-Mediated Translation and Its Potential for Novel mRNA-Based Therapy Development

Abstract

Many conditions can benefit from RNA-based therapies, namely, those targeting internal ribosome entry sites (IRESs) and their regulatory proteins, the IRES trans-acting factors (ITAFs). IRES-mediated translation is an alternative mechanism of translation initiation, known for maintaining protein synthesis when canonical translation is impaired. During a stress response, it contributes to cell reprogramming and adaptation to the new environment. The relationship between IRESs and ITAFs with tumorigenesis and resistance to therapy has been studied in recent years, proposing new therapeutic targets and treatments. In addition, IRES-dependent translation initiation dysregulation is also related to neurological and cardiovascular diseases, muscular atrophies, or other syndromes. The participation of these structures in the development of such pathologies has been studied, yet to a far lesser extent than in cancer. Strategies involving the disruption of IRES–ITAF interactions or the modification of ITAF expression levels may be used with great impact in the development of new therapeutics. In this review, we aim to comprehend the current data on groups of human pathologies associated with IRES and/or ITAF dysregulation and their application in the designing of new therapeutic approaches using them as targets or tools. Thus, we wish to summarise the evidence in the field hoping to open new promising lines of investigation toward personalised treatments.

Diurnal rhythmicity of wearable device-measured wrist temperature predicts future disease incidence in the UK Biobank

“…IRES elements are found in about 10% of human 5'UTRs 54 . Dysregulation of this IRES-mediated translation in distinct transcripts, such as insulin-like growth factor 1 (IGF-1) receptor, are implicated under certain conditions with the corresponding pathology, i.e., diabetes (as suggested in Marques et al 55 ), pointing towards the clinical relevance of this pathway. In a cell culture model, IRESspeci c translation was instrumental for murine Per1 oscillations 56 , a core regulator of the clock's transcriptional feedback loop.…”

AGEs induce high expression of Dll4 via endoplasmic reticulum stress PERK signaling-mediated internal ribosomal entry site mechanism in macrophages

“…Thus, it is highly probable that there would be alternative mechanisms to bypass ER stress-inhibited canonical cap-dependent translation. In mammals, IRES located in 5′UTR of mRNA could initiate protein translation when cap-dependent mechanism is globally suspended in cells under stressful conditions [ 19 ]. This mechanism could be a reasonable interpretation.…”

Structure and function of type IV IRES in picornaviruses: a systematic review

“…Cellular proteins binding to viral IRES are critical for orchestrating the life cycle of viruses. For example, certain cellular proteins can enhance the activity of IRES, while others may suppress its function (Liu et al, 2020;Embarc-Buh et al, 2021;Lopez-Ulloa et al, 2022;Marques et al, 2022). During this process, the secondary and tertiary structures of IRES constitute the foundation for the interaction with various cellular factors.…”