A translating ribosome is typically thought to follow the reading frame defined by the selected
start codon. Using super-resolution ribosome profiling, here we report pervasive out-of-frame translation immediately from the
start codon. The
start codon-associated ribosome frameshifting (SCARF) stems from the slippage of ribosomes during the transition from initiation to elongation. Using a massively paralleled reporter assay, we uncovered sequence elements acting as SCARF enhancers or repressors, implying that
start codon recognition is coupled with reading frame fidelity. This finding explains thousands of mass spectrometry spectra unannotated from human
proteome. Mechanistically, we find that the eukaryotic
initiation factor 5B (
eIF5B) maintains the reading frame fidelity by stabilizing initiating ribosomes. Intriguingly,
amino acid starvation induces SCARF by proteasomal degradation of
eIF5B. The stress-induced SCARF protects cells from
starvation by enabling
amino acid recycling and selective mRNA translation. Our findings illustrate a beneficial effect of translational "noise" in nutrient stress adaptation.