Inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response

Biochem J. 2012 Mar 15;442(3):639-48. doi: 10.1042/BJ20111220.


Selective small-molecule inhibitors represent powerful tools for the dissection of complex biological processes. ES(I) (eeyarestatin I) is a novel modulator of ER (endoplasmic reticulum) function. In the present study, we show that in addition to acutely inhibiting ERAD (ER-associated degradation), ES(I) causes production of mislocalized polypeptides that are ubiquitinated and degraded. Unexpectedly, our results suggest that these non-translocated polypeptides promote activation of the UPR (unfolded protein response), and indeed we can recapitulate UPR activation with an alternative and quite distinct inhibitor of ER translocation. These results suggest that the accumulation of non-translocated proteins in the cytosol may represent a novel mechanism that contributes to UPR activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytosol / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum / metabolism*
  • HeLa Cells
  • Humans
  • Hydrazones / metabolism
  • Hydroxyurea / analogs & derivatives
  • Hydroxyurea / metabolism
  • Peptides / chemistry
  • Peptides / metabolism
  • Protein Folding
  • Protein Transport*
  • Transfection
  • Ubiquitin / metabolism
  • Unfolded Protein Response / physiology*


  • 1-(4-chlorophenyl)-3-(3-(4-chlorophenyl)-5,5-dimethyl-1-(3-(5-nitrofuran-2-yl)allyldienehydrazinocarbonylmethyl)-2-oxoimidazolidin-4-yl)-1-hydroxyurea
  • DNA-Binding Proteins
  • Hydrazones
  • Peptides
  • Ubiquitin
  • Hydroxyurea