A ribosome-bound quality control complex triggers degradation of nascent peptides and signals translation stress

Cell. 2012 Nov 21;151(5):1042-54. doi: 10.1016/j.cell.2012.10.044.

Abstract

The conserved transcriptional regulator heat shock factor 1 (Hsf1) is a key sensor of proteotoxic and other stress in the eukaryotic cytosol. We surveyed Hsf1 activity in a genome-wide loss-of-function library in Saccaromyces cerevisiae as well as ~78,000 double mutants and found Hsf1 activity to be modulated by highly diverse stresses. These included disruption of a ribosome-bound complex we named the Ribosome Quality Control Complex (RQC) comprising the Ltn1 E3 ubiquitin ligase, two highly conserved but poorly characterized proteins (Tae2 and Rqc1), and Cdc48 and its cofactors. Electron microscopy and biochemical analyses revealed that the RQC forms a stable complex with 60S ribosomal subunits containing stalled polypeptides and triggers their degradation. A negative feedback loop regulates the RQC, and Hsf1 senses an RQC-mediated translation-stress signal distinctly from other stresses. Our work reveals the range of stresses Hsf1 monitors and elucidates a conserved cotranslational protein quality control mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Cell Cycle Proteins / metabolism
  • DNA-Binding Proteins / genetics
  • Heat-Shock Proteins / genetics
  • Multiprotein Complexes / metabolism*
  • Peptides / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Biosynthesis*
  • RNA-Binding Proteins
  • Ribosomes / metabolism*
  • Saccharomyces cerevisiae / cytology
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Stress, Physiological
  • Transcription Factors / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Valosin Containing Protein

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • HSF1 protein, S cerevisiae
  • Heat-Shock Proteins
  • Multiprotein Complexes
  • Peptides
  • RNA-Binding Proteins
  • Rqc1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Tae2 protein, S cerevisiae
  • Transcription Factors
  • Ltn1 protein, S cerevisiae
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex
  • Adenosine Triphosphatases
  • CDC48 protein, S cerevisiae
  • Valosin Containing Protein