title: Inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response.
abstract: 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.
authors.affiliation: Faculty of Life Sciences, University of Manchester, UK.
authors.forename: Craig
authors.initials: C
authors.lastname: McKibbin
authors.forename: Alina
authors.initials: A
authors.lastname: Mares
authors.forename: Michela
authors.initials: M
authors.lastname: Piacenti
authors.forename: Helen
authors.initials: H
authors.lastname: Williams
authors.forename: Peristera
authors.initials: P
authors.lastname: Roboti
authors.forename: Marjo
authors.initials: M
authors.lastname: Puumalainen
authors.forename: Anna C
authors.initials: AC
authors.lastname: Callan
authors.forename: Karolina
authors.initials: K
authors.lastname: Lesiak-Mieczkowska
authors.forename: Stig
authors.initials: S
authors.lastname: Linder
authors.forename: Hanna
authors.initials: H
authors.lastname: Harant
authors.forename: Stephen
authors.initials: S
authors.lastname: High
authors.forename: Sabine L
authors.initials: SL
authors.lastname: Flitsch
authors.forename: Roger C
authors.initials: RC
authors.lastname: Whitehead
authors.forename: Eileithyia
authors.initials: E
authors.lastname: Swanton
mesh_terms: D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D006835:Hydrazones / Q000378:metabolism; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding; D021381:Protein Transport; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: C492847:1-(4-chlorophenyl)-3-(3-(4-chlorophenyl)-5,5-dimethyl-1-(3-(5-nitrofuran-2-yl)allyldienehydrazinocarbonylmethyl)-2-oxoimidazolidin-4-yl)-1-hydroxyurea; D004268:DNA-Binding Proteins; D006835:Hydrazones; D010455:Peptides; D025801:Ubiquitin; D006918:Hydroxyurea