Protein Synthesis Initiation in Eukaryotes:IRES‐mediated Internal Initiation

Abstract

The major mechanism of translation initiation in eukaryotes involves recognition of the cap structure at the 5′ end of the mRNA by the cap‐binding protein eIF4E. Internal ribosome entry sites (IRES) are specialised RNA sequences that are capable of recruiting ribosomes to an internal position of an mRNA in a cap‐independent manner. Many viruses have evolved this alternative pathway to initiate translation. Viral IRESs bind ribosomes by several mechanisms that require different sets of canonical initiation factors. In addition, IRES activity is modulated by IRES trans‐acting factors (ITAFs). Some cellular mRNAs are suggested to contain IRESs, as they function in cells under stress and other conditions when cap‐dependent initiation is inhibited. However, solid evidence for internal ribosome entry onto many of these mRNAs is lacking. Key Concepts In eukaryotes, the majority of mRNAs are translated by a 5′ end‐dependent mechanism, in which the mRNA 5′ cap structure recruits the translation machinery. Specific RNA elements, termed internal ribosome entry sites (IRESs), can direct ribosomes to internal positions of mRNAs to initiate translation. IRESs in viral RNA genomes differ significantly with respect to their structure and initiation factor requirements. In addition to some canonical initiation factors, IRES‐mediated translation may require ITAFs (IRES trans ‐acting factors). Many cellular mRNAs are suggested to possess IRESs, as they remain active under a number of pathophysiological stress conditions when cap‐dependent translation is inhibited. The authenticity of some cellular IRESs remains controversial as being not confirmed in recently developed stringent tests for IRES activity.

Hydrogen peroxide sensitivity connects the activity of COX5A and NPR3 to the regulation of YAP1 expression

“…81 However, it is crucial for the cell to translate mRNAs whose protein products are required for cell survival under the stress condition. 82 One such mRNA is YAP1 that benefits from the alternative mode of translation initiation under oxidative stress through its IRES which is a regulatory element located on its 5′ UTR. 53 IRESs are elements that can enable selective translation in a cap-independent manner with coordination of ITAFs.…”

“…Under certain stress conditions like oxidative stress, cap‐dependent initiation is inhibited, leading to the global suppression of canonical translation 81 . However, it is crucial for the cell to translate mRNAs whose protein products are required for cell survival under the stress condition 82 . One such mRNA is YAP1 that benefits from the alternative mode of translation initiation under oxidative stress through its IRES which is a regulatory element located on its 5′ UTR 53 .…”

Viruses as archaeological tools for uncovering ancient molecular relationships

“…103,104 In some examples where complete eIF4G is not available, its function may be replaced by either a fragment of it or a related protein. 105 In contrast, HCV and related animal pestiviruses only need eIF2 to introduce the initiator amino acid, and the insect dicistrovirus cricket paralysis virus (CrPV) can initiate protein synthesis in the absence of any initiation factors. 106 The different viral initiation modes have been classified mainly according to their initiation factor dependence, 107 which reflects a spectrum of possibilities to bypass the standard requirements for protein initiation.…”

“…Alternative cap‐independent mechanisms for initiating translation in cellular mRNAs have been described, which include certain mRNAs that use an IRES element, although these are likely to require all the canonical eIFs except for eIF4E, the factor that binds to the mRNA cap 103,104 . In some examples where complete eIF4G is not available, its function may be replaced by either a fragment of it or a related protein 105 . In contrast, HCV and related animal pestiviruses only need eIF2 to introduce the initiator amino acid, and the insect dicistrovirus cricket paralysis virus (CrPV) can initiate protein synthesis in the absence of any initiation factors 106 .…”

In Vitro Transcribed RNA-Based Platform Vaccines: Past, Present, and Future

“…These IRESs structurally mimic Met-tRNAi. Cricket paralysis virus (CrPV) and Taura syndrome virus (TSV) are prominent examples of Class IV IRESs [50][51][52][53]. It is noteworthy that viral IRESs incorporated into IVT mRNAs have demonstrated higher protein production levels compared to cellular IRESs such as eukaryotic initiation factor 4G (eIF4G), fragile X Messenger Ribonucleoprotein 1 (FMR1), or connexin 43 (CN43) [50].…”