title: Cotranslational response to proteotoxic stress by elongation pausing of ribosomes.
abstract: Translational control permits cells to respond swiftly to a changing environment. Rapid attenuation of global protein synthesis under stress conditions has been largely ascribed to the inhibition of translation initiation. Here we report that intracellular proteotoxic stress reduces global protein synthesis by halting ribosomes on transcripts during elongation. Deep sequencing of ribosome-protected messenger RNA (mRNA) fragments reveals an early elongation pausing, roughly at the site where nascent polypeptide chains emerge from the ribosomal exit tunnel. Inhibiting endogenous chaperone molecules by a dominant-negative mutant or chemical inhibitors recapitulates the early elongation pausing, suggesting a dual role of molecular chaperones in facilitating polypeptide elongation and cotranslational folding. Our results further support the chaperone "trapping" mechanism in promoting the passage of nascent chains. Our study reveals that translating ribosomes fine tune the elongation rate by sensing the intracellular folding environment. The early elongation pausing represents a cotranslational stress response to maintain the intracellular protein homeostasis.
authors.affiliation: Graduate Field of Genetics, Genomics & Development, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Botao
authors.initials: B
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Han
authors.forename: Shu-Bing
authors.initials: SB
authors.lastname: Qian
mesh_terms: D005799:Genes, Dominant; D057809:HEK293 Cells; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D010441:Peptide Chain Elongation, Translational / Q000187:drug effects*; D011506:Proteins / Q000633:toxicity*; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects*
chemical_list: D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D011506:Proteins