Deletion of the fission yeast homologue of human insulinase reveals a TORC1-dependent pathway mediating resistance to proteotoxic stress.
Insulin Degrading Enzyme (IDE) is a protease conserved through evolution with a role in diabetes and Alzheimer's disease. The reason underlying its ubiquitous expression including cells lacking identified IDE substrates remains unknown. Here we show that the fission yeast IDE homologue (Iph1) m...
Guardado en:
| Autores principales: | , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2013
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/712f3f0182c74f95862e94901ffc7dac |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:712f3f0182c74f95862e94901ffc7dac |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:712f3f0182c74f95862e94901ffc7dac2021-11-18T07:40:15ZDeletion of the fission yeast homologue of human insulinase reveals a TORC1-dependent pathway mediating resistance to proteotoxic stress.1932-620310.1371/journal.pone.0067705https://doaj.org/article/712f3f0182c74f95862e94901ffc7dac2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23826334/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Insulin Degrading Enzyme (IDE) is a protease conserved through evolution with a role in diabetes and Alzheimer's disease. The reason underlying its ubiquitous expression including cells lacking identified IDE substrates remains unknown. Here we show that the fission yeast IDE homologue (Iph1) modulates cellular sensitivity to endoplasmic reticulum (ER) stress in a manner dependent on TORC1 (Target of Rapamycin Complex 1). Reduced sensitivity to tunicamycin was associated with a smaller number of cells undergoing apoptosis. Wild type levels of tunicamycin sensitivity were restored in iph1 null cells when the TORC1 complex was inhibited by rapamycin or by heat inactivation of the Tor2 kinase. Although Iph1 cleaved hallmark IDE substrates including insulin efficiently, its role in the ER stress response was independent of its catalytic activity since expression of inactive Iph1 restored normal sensitivity. Importantly, wild type as well as inactive human IDE complemented gene-invalidated yeast cells when expressed at the genomic locus under the control of iph1(+) promoter. These results suggest that IDE has a previously unknown function unrelated to substrate cleavage, which links sensitivity to ER stress to a pro-survival role of the TORC1 pathway.Clémentine BeuzelinIrini EvnouchidouPascal RigoletAnne Cauvet-BurgevinPierre-Marie GirardDelphine DardalhonSlobodan CulinaAbdelaziz GdouraPeter van EndertStefania FrancesconiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 6, p e67705 (2013) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Clémentine Beuzelin Irini Evnouchidou Pascal Rigolet Anne Cauvet-Burgevin Pierre-Marie Girard Delphine Dardalhon Slobodan Culina Abdelaziz Gdoura Peter van Endert Stefania Francesconi Deletion of the fission yeast homologue of human insulinase reveals a TORC1-dependent pathway mediating resistance to proteotoxic stress. |
| description |
Insulin Degrading Enzyme (IDE) is a protease conserved through evolution with a role in diabetes and Alzheimer's disease. The reason underlying its ubiquitous expression including cells lacking identified IDE substrates remains unknown. Here we show that the fission yeast IDE homologue (Iph1) modulates cellular sensitivity to endoplasmic reticulum (ER) stress in a manner dependent on TORC1 (Target of Rapamycin Complex 1). Reduced sensitivity to tunicamycin was associated with a smaller number of cells undergoing apoptosis. Wild type levels of tunicamycin sensitivity were restored in iph1 null cells when the TORC1 complex was inhibited by rapamycin or by heat inactivation of the Tor2 kinase. Although Iph1 cleaved hallmark IDE substrates including insulin efficiently, its role in the ER stress response was independent of its catalytic activity since expression of inactive Iph1 restored normal sensitivity. Importantly, wild type as well as inactive human IDE complemented gene-invalidated yeast cells when expressed at the genomic locus under the control of iph1(+) promoter. These results suggest that IDE has a previously unknown function unrelated to substrate cleavage, which links sensitivity to ER stress to a pro-survival role of the TORC1 pathway. |
| format |
article |
| author |
Clémentine Beuzelin Irini Evnouchidou Pascal Rigolet Anne Cauvet-Burgevin Pierre-Marie Girard Delphine Dardalhon Slobodan Culina Abdelaziz Gdoura Peter van Endert Stefania Francesconi |
| author_facet |
Clémentine Beuzelin Irini Evnouchidou Pascal Rigolet Anne Cauvet-Burgevin Pierre-Marie Girard Delphine Dardalhon Slobodan Culina Abdelaziz Gdoura Peter van Endert Stefania Francesconi |
| author_sort |
Clémentine Beuzelin |
| title |
Deletion of the fission yeast homologue of human insulinase reveals a TORC1-dependent pathway mediating resistance to proteotoxic stress. |
| title_short |
Deletion of the fission yeast homologue of human insulinase reveals a TORC1-dependent pathway mediating resistance to proteotoxic stress. |
| title_full |
Deletion of the fission yeast homologue of human insulinase reveals a TORC1-dependent pathway mediating resistance to proteotoxic stress. |
| title_fullStr |
Deletion of the fission yeast homologue of human insulinase reveals a TORC1-dependent pathway mediating resistance to proteotoxic stress. |
| title_full_unstemmed |
Deletion of the fission yeast homologue of human insulinase reveals a TORC1-dependent pathway mediating resistance to proteotoxic stress. |
| title_sort |
deletion of the fission yeast homologue of human insulinase reveals a torc1-dependent pathway mediating resistance to proteotoxic stress. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/712f3f0182c74f95862e94901ffc7dac |
| work_keys_str_mv |
AT clementinebeuzelin deletionofthefissionyeasthomologueofhumaninsulinaserevealsatorc1dependentpathwaymediatingresistancetoproteotoxicstress AT irinievnouchidou deletionofthefissionyeasthomologueofhumaninsulinaserevealsatorc1dependentpathwaymediatingresistancetoproteotoxicstress AT pascalrigolet deletionofthefissionyeasthomologueofhumaninsulinaserevealsatorc1dependentpathwaymediatingresistancetoproteotoxicstress AT annecauvetburgevin deletionofthefissionyeasthomologueofhumaninsulinaserevealsatorc1dependentpathwaymediatingresistancetoproteotoxicstress AT pierremariegirard deletionofthefissionyeasthomologueofhumaninsulinaserevealsatorc1dependentpathwaymediatingresistancetoproteotoxicstress AT delphinedardalhon deletionofthefissionyeasthomologueofhumaninsulinaserevealsatorc1dependentpathwaymediatingresistancetoproteotoxicstress AT slobodanculina deletionofthefissionyeasthomologueofhumaninsulinaserevealsatorc1dependentpathwaymediatingresistancetoproteotoxicstress AT abdelazizgdoura deletionofthefissionyeasthomologueofhumaninsulinaserevealsatorc1dependentpathwaymediatingresistancetoproteotoxicstress AT petervanendert deletionofthefissionyeasthomologueofhumaninsulinaserevealsatorc1dependentpathwaymediatingresistancetoproteotoxicstress AT stefaniafrancesconi deletionofthefissionyeasthomologueofhumaninsulinaserevealsatorc1dependentpathwaymediatingresistancetoproteotoxicstress |
| _version_ |
1718423103964446720 |