EDF1 coordinates cellular responses to ribosome collisions

Elife. 2020 Aug 3;9:e58828. doi: 10.7554/eLife.58828.

Abstract

Translation of aberrant mRNAs induces ribosomal collisions, thereby triggering pathways for mRNA and nascent peptide degradation and ribosomal rescue. Here we use sucrose gradient fractionation combined with quantitative proteomics to systematically identify proteins associated with collided ribosomes. This approach identified Endothelial differentiation-related factor 1 (EDF1) as a novel protein recruited to collided ribosomes during translational distress. Cryo-electron microscopic analyses of EDF1 and its yeast homolog Mbf1 revealed a conserved 40S ribosomal subunit binding site at the mRNA entry channel near the collision interface. EDF1 recruits the translational repressors GIGYF2 and EIF4E2 to collided ribosomes to initiate a negative-feedback loop that prevents new ribosomes from translating defective mRNAs. Further, EDF1 regulates an immediate-early transcriptional response to ribosomal collisions. Our results uncover mechanisms through which EDF1 coordinates multiple responses of the ribosome-mediated quality control pathway and provide novel insights into the intersection of ribosome-mediated quality control with global transcriptional regulation.

Keywords: biochemistry; cell biology; chemical biology; human; quality control; ribosomal collisions; ribosome; transcriptional response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calmodulin-Binding Proteins / genetics*
  • Calmodulin-Binding Proteins / metabolism
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Protein Biosynthesis / physiology*
  • Ribosomes / physiology*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Calmodulin-Binding Proteins
  • EDF1 protein, human
  • MBF1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors

Associated data

  • GEO/GSE149565