The diversity, plasticity, and adaptability of cap-dependent translation initiation and the associated machinery

Translation initiation is a critical facet of gene expression with important impacts that underlie cellular responses to stresses and environmental cues. Its dysregulation in many diseases position this process as an important area for the development of new therapeutics. The gateway translation factor eIF4E is typically considered responsible for 'global' or 'canonical' m⁷G cap-dependent translation. However, eIF4E impacts translation of specific transcripts rather than the entire translatome. There are many alternative cap-dependent translation mechanisms that also contribute to the translation capacity of the cell. We review the diversity of these, juxtaposing more recently identified mechanisms with eIF4E-dependent modalities. We also explore the multiplicity of functions played by translation factors, both within and outside protein synthesis, and discuss how these differentially contribute to their ultimate physiological impacts. For comparison, we discuss some modalities for cap-independent translation. In all, this review highlights the diverse mechanisms that engage and control translation in eukaryotes.