Protein Synthesis Initiation in Eukaryotes: IRES‐mediated Internal Initiation

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. Keywords: cap structure; eukaryotic mRNA; initiation factors; IRES; ITAF; picornaviruses; protein synthesis; ribosome; translation initiation