capdependent

Cap-dependent translation refers to the primary mechanism by which eukaryotic cells initiate translation of most mRNAs, requiring a 5' mRNA cap, typically the 7-methylguanosine cap (m7GpppN). The cap is recognized by the cap-binding protein eIF4E, which forms the eIF4F complex with the scaffold protein eIF4G and the helicase eIF4A. The eIF4F complex recruits the 43S preinitiation complex to the 5' end and, after initiation, the ribosome scans the 5' untranslated region to locate the start codon. mRNA circularization, mediated by interactions between eIF4G and poly(A)-binding protein (PABP), promotes efficient reinitiation of translation.

Cap-dependent initiation is regulated by signaling pathways, particularly mTOR, which controls eIF4E availability through 4E-BP phosphorylation. When 4E-BPs are hypophosphorylated, they sequester eIF4E and repress cap-dependent translation. Environmental cues such as nutrient status, growth signals, and stress affect this balance, altering global protein synthesis.

Although cap-dependent translation supports the majority of cellular mRNAs, it is sensitive to stress and energy status. Under certain stress conditions, phosphorylation of eIF2α and reduced cap-dependent activity can lead to reliance on cap-independent mechanisms, including internal ribosome entry sites (IRES), for a subset of mRNAs.

Dysregulation of cap-dependent translation, such as eIF4E overexpression or hyperactive mTOR signaling, is associated with oncogenesis and other diseases, underscoring the importance of cap recognition in controlling protein synthesis. Some viruses exploit or disrupt cap-dependent translation to prioritize viral mRNA.