EIF5B is a ribosome-dependent GTPase that plays a critical role in eukaryotic translation initiation by promoting 60S ribosomal subunit joining to the preinitiation complex to form the 80S initiation complex 1. Working in concert with eIF1A, eIF5B reorients the initiator methionine-tRNA into a conformation compatible with ribosomal subunit joining 2. While GTP hydrolysis is not strictly required for subunit joining, GTP hydrolysis is essential for rapid ejection of eIF1A and subsequent eIF5B release, enabling formation of elongation-competent ribosomes 1. eIF5B competes with eIF1A for binding to eIF5B, and this competition may coordinate the transition between start codon selection and subunit joining steps 3. Beyond canonical translation, eIF5B regulates stress-responsive translation: integrated stress response activation drives eIF5B-dependent translation of PD-L1, an immune checkpoint ligand frequently upregulated in lung adenocarcinomas associated with poor prognosis 4. Under nutrient stress, proteasomal degradation of eIF5B compromises reading frame fidelity, enabling selective amino acid recycling and adaptation 5. eIF5B also supports HCV IRES-dependent translation under conditions limiting canonical eIF2 availability 6, highlighting its role as an alternative initiation factor during cellular stress.