Cap-Independent Translation: What’s in a Name?

Eukaryotic translation initiation relies on the m7G cap present at the 5′ end of all mRNAs. Some viral mRNAs employ alternative mechanisms of initiation based on internal ribosome entry. The ‘IRES ideology’ was adopted by researchers to explain the differential translation of cellular mRNAs when the cap recognition is suppressed. However, some cellular IRESs have already been challenged and others are awaiting their validation. As an alternative cap-independent mechanism, we propose adopting the concept of cap-independent translation enhancers (CITEs) for mammalian mRNAs. Unlike IRESs, CITEs can be located both within 5′ and 3′ UTRs and bind mRNA-recruiting translational components. The respective 5′ UTRs are then inspected by the scanning machinery essentially in the same way as under cap-dependent translation. The eukaryotic translation initiation relies not only on the cap-dependent mechanism of mRNA binding to the ribosome, but also on poorly studied cap-independent ways of recruiting mRNAs to ribosomes. The latter mode plays an important role in cell differentiation and cellular response to abnormal conditions. The widely adopted way to explain the cap-independent translation of cellular mRNAs is the use of internal ribosome entry sites (IRESs). However, some of the cap-independent mechanisms cannot be explained with the IRES concept. This review proposes an alternative mechanism for cap-independent initiation. It is based on the presence (in the UTRs of mRNAs) of structural elements that bind the factors recruiting mRNAs to the ribosome cap-independent translational enhancers (CITEs). This mechanism is supported by recent reports. By binding components of the translation machinery, CITEs help specific mRNAs to win the competition for ribosomes.