Elongation factor P controls ribosomal frameshift of a Salmonella antimicrobial resistance gene

Ribosomes translate mRNAs by matching every 3-nucleotide sequence in mRNA, producing the corresponding proteins. As the amino acid sequence directly dictates the activity of the protein, frameshifts often lead to unexpected effects. Here, ribosome profiling reveals that the intracellular pathogen Salmonella Typhimurium suppresses frameshift in the ugtL antimicrobial resistance gene during translation. This suppression of frameshift is mediated by a ribosome pause occurring in a newly-identified overlapping gene, serving as a non-slip bump. Given that the pause site contains a poly-proline motif and can be resolved by elongation factor P, the removal of the ribosome pause by substituting the motif induces ribosome slippage in ugtL, resulting in UgtL frameshifted protein production. This renders Salmonella sensitive to antimicrobial peptides but, in turn, protects the MgtC virulence factor from the FtsH-mediated proteolysis, indicating that elongation factor P-dependent ribosome pause is required for controlling both full antimicrobial resistance and mouse virulence. These findings reveal a new regulatory mechanism in which ribosome pause controls the production of two different protein isoforms by suppressing ribosome slippage-mediated frameshift.