Abstract
Molecular chaperones assist in protein folding by interacting with nascent polypeptide chains (NCs) during translation. Whether the ribosome can sense chaperone defects and abort translation of misfolding NCs has not yet been explored. Here we used quantitative proteomics in E. coli to investigate the ribosome-associated chaperone network and the consequences of its dysfunction. Trigger factor and the DnaK (Hsp70) system are the major NC-binding chaperones. HtpG (Hsp90), GroEL and ClpB contribute increasingly, when DnaK is deficient. Surprisingly, misfolding of NCs due to defects in co-translational chaperone function or amino acid analog incorporation, results in recruitment of the non-canonical release factor RF3 to the ribosome. RF3 then cooperates with RF2 in mediating premature chain termination of a subset of abundant NCs, facilitating clearance by degradation. This function of RF3 efficiently reduces the accumulation of misfolded proteins. It is critical for proteostasis maintenance and cell survival under conditions of limited chaperone availability.
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