Alternative ways to think about mRNA sequences and proteins that appear to promote internal initiation of translation.

Translation of some mRNAs is postulated to occur via an internal initiation mechanism which is said to be augmented by a variety of RNA-binding proteins. A pervasive problem is that the RNA sequences to which the proteins bind were not rigorously proven to function as internal ribosome entry sites (IRESs). Critical examination of the evidence reveals flaws that leave room for alternative interpretations, such as the possibility that IRES elements might function as cryptic promoters, splice sites, or sequences that modulate cleavage by RNases. The growing emphasis on IRES-binding proteins diverts attention from these fundamental unresolved issues. Many of the putative IRES-binding proteins are heterogeneous nuclear ribonucleoproteins that have recognized roles in RNA processing or stability and no recognized role in translation. Thus the mechanism whereby they promote internal initiation, if indeed they do, is not obvious. Some recent experiments were said to support the idea that IRES-binding proteins cause functionally important changes in folding of the RNA, but the evidence is not convincing when examined closely. The proteins that bind to some (not all) viral IRES elements include a subset of authentic initiation factors. This has not been demonstrated with any candidate IRES of cellular origin, however; and even with viral RNAs, the required chase experiment has not been done to prove that a pre-bound initiation factor actually mediates subsequent entry of ribosomes. In short, the focus on IRES-binding proteins has gotten us no closer to understanding the mechanism of internal initiation. Given the aforementioned uncertainty about whether other mechanisms (splicing, cryptic promoters) might underlie what-appears-to-be internal initiation, a temporary solution might be to redefine IRES to mean "internal regulatory expression sequence." This compromise would allow the sequences to be used for gene expression studies, for which they sometimes work, without asserting more than has been proven about the mechanism.