Copper-controlled gene expression via transmembrane-induced ribosomal stalling

Regulated gene expression in response to metabolite sensing is a fundamental process for cellular adaptation and survival. Cells have developed diverse strategies to detect and respond to various metabolites in their environment. Here, we have identified a post-transcriptional mechanism in Rhodobacter capsulatus that integrates the periplasmic Cu concentration into the translational control of the copper detoxifying enzyme CutO. This is achieved through Cu-induced stalling of the nascent CutF protein inside the ribosomal peptide tunnel during co-translational secretion. Stalling at a C-terminal proline-rich motif overrides the function of elongation factor P (EF-P) and allows melting of an mRNA stem-loop that shields the cutO ribosome-binding site. Thus, CutF acts as a transmembrane Cu sensor that controls CutO production via ribosomal stalling. Considering that CutF is a member of the widely distributed bacterial DUF2946 protein family, the mechanism identified here likely represents a conserved bacterial strategy for adapting to toxic heavy metals.