Cargando…

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

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),...

Descripción completa

Detalles Bibliográficos
Autores principales: McKibbin, Craig, Mares, Alina, Piacenti, Michela, Williams, Helen, Roboti, Peristera, Puumalainen, Marjo, Callan, Anna C., Lesiak-Mieczkowska, Karolina, Linder, Stig, Harant, Hanna, High, Stephen, Flitsch, Sabine L., Whitehead, Roger C., Swanton, Eileithyia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286858/
https://www.ncbi.nlm.nih.gov/pubmed/22145777
http://dx.doi.org/10.1042/BJ20111220
_version_ 1782224594598363136
author McKibbin, Craig
Mares, Alina
Piacenti, Michela
Williams, Helen
Roboti, Peristera
Puumalainen, Marjo
Callan, Anna C.
Lesiak-Mieczkowska, Karolina
Linder, Stig
Harant, Hanna
High, Stephen
Flitsch, Sabine L.
Whitehead, Roger C.
Swanton, Eileithyia
author_facet McKibbin, Craig
Mares, Alina
Piacenti, Michela
Williams, Helen
Roboti, Peristera
Puumalainen, Marjo
Callan, Anna C.
Lesiak-Mieczkowska, Karolina
Linder, Stig
Harant, Hanna
High, Stephen
Flitsch, Sabine L.
Whitehead, Roger C.
Swanton, Eileithyia
author_sort McKibbin, Craig
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3286858
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Portland Press Ltd.
record_format MEDLINE/PubMed
spelling pubmed-32868582012-03-05 Inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response McKibbin, Craig Mares, Alina Piacenti, Michela Williams, Helen Roboti, Peristera Puumalainen, Marjo Callan, Anna C. Lesiak-Mieczkowska, Karolina Linder, Stig Harant, Hanna High, Stephen Flitsch, Sabine L. Whitehead, Roger C. Swanton, Eileithyia Biochem J Research Article 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. Portland Press Ltd. 2012-02-24 2012-03-15 /pmc/articles/PMC3286858/ /pubmed/22145777 http://dx.doi.org/10.1042/BJ20111220 Text en © 2012 The Author(s) The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by-nc/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
McKibbin, Craig
Mares, Alina
Piacenti, Michela
Williams, Helen
Roboti, Peristera
Puumalainen, Marjo
Callan, Anna C.
Lesiak-Mieczkowska, Karolina
Linder, Stig
Harant, Hanna
High, Stephen
Flitsch, Sabine L.
Whitehead, Roger C.
Swanton, Eileithyia
Inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response
title Inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response
title_full Inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response
title_fullStr Inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response
title_full_unstemmed Inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response
title_short Inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response
title_sort inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286858/
https://www.ncbi.nlm.nih.gov/pubmed/22145777
http://dx.doi.org/10.1042/BJ20111220
work_keys_str_mv AT mckibbincraig inhibitionofproteintranslocationattheendoplasmicreticulumpromotesactivationoftheunfoldedproteinresponse
AT maresalina inhibitionofproteintranslocationattheendoplasmicreticulumpromotesactivationoftheunfoldedproteinresponse
AT piacentimichela inhibitionofproteintranslocationattheendoplasmicreticulumpromotesactivationoftheunfoldedproteinresponse
AT williamshelen inhibitionofproteintranslocationattheendoplasmicreticulumpromotesactivationoftheunfoldedproteinresponse
AT robotiperistera inhibitionofproteintranslocationattheendoplasmicreticulumpromotesactivationoftheunfoldedproteinresponse
AT puumalainenmarjo inhibitionofproteintranslocationattheendoplasmicreticulumpromotesactivationoftheunfoldedproteinresponse
AT callanannac inhibitionofproteintranslocationattheendoplasmicreticulumpromotesactivationoftheunfoldedproteinresponse
AT lesiakmieczkowskakarolina inhibitionofproteintranslocationattheendoplasmicreticulumpromotesactivationoftheunfoldedproteinresponse
AT linderstig inhibitionofproteintranslocationattheendoplasmicreticulumpromotesactivationoftheunfoldedproteinresponse
AT haranthanna inhibitionofproteintranslocationattheendoplasmicreticulumpromotesactivationoftheunfoldedproteinresponse
AT highstephen inhibitionofproteintranslocationattheendoplasmicreticulumpromotesactivationoftheunfoldedproteinresponse
AT flitschsabinel inhibitionofproteintranslocationattheendoplasmicreticulumpromotesactivationoftheunfoldedproteinresponse
AT whiteheadrogerc inhibitionofproteintranslocationattheendoplasmicreticulumpromotesactivationoftheunfoldedproteinresponse
AT swantoneileithyia inhibitionofproteintranslocationattheendoplasmicreticulumpromotesactivationoftheunfoldedproteinresponse