Beyond Translation Initiation: Translational Elongation, Decoding Fidelity, and Ribosome Surveillance During Branched-Chain Amino Acid Deprivation, with a Focus on Mammalian Systems

In mammalian systems, translational responses to amino acid limitation are commonly framed as mechanistic target of rapamycin complex 1 (mTORC1) inhibition and activation of the general control nonderepressible 2 (GCN2)–eukaryotic initiation factor 2α (eIF2α) arm of the integrated stress response. Suppressing initiation, however, does not immediately relieve aminoacylated transfer RNA shortages for ribosomes already engaged on messenger RNA. Transfer RNA charging and ribosome profiling reveal codon- and isoacceptor-specific elongation constraints. Across mouse NIH3T3 and several human cell systems, leucine deprivation often appears initiation-dominant but can produce UUA-biased pausing and frameshifting in selected cancer cells. Valine deprivation can prolong decoding at all four valine codons, whereas separate isoleucine-deprivation studies report AUU/AUC-selective slowing, a cytoplasmic isoleucyl-tRNA synthetase 1 (IARS1)-linked isoleucine-to-valine signal in exogenous reporter peptides, and an isoleucine-to-methionine substitution signal of unresolved mechanism. Ribosome slowing can engage global, transcript-local, and quality-control feedback, but the inputs are stress- and system-dependent. We propose a two-layer kinetic framework separating (i) A-site competition among correct decoding, substitution, and abortive exit from (ii) collision formation set by ribosome influx and dwell time. It keeps protein quantity, sequence fidelity, retained function, and proteostasis cost separate, and defines a matched measurement roadmap from metabolite flux to protein function.