title: Deletion of the fission yeast homologue of human insulinase reveals a TORC1-dependent pathway mediating resistance to proteotoxic stress.
abstract: 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.
authors.affiliation: Institut Curie, Centre de Recherche, Orsay, France.
authors.forename: Clémentine
authors.initials: C
authors.lastname: Beuzelin
authors.forename: Irini
authors.initials: I
authors.lastname: Evnouchidou
authors.forename: Pascal
authors.initials: P
authors.lastname: Rigolet
authors.forename: Anne
authors.initials: A
authors.lastname: Cauvet-Burgevin
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Girard
authors.forename: Delphine
authors.initials: D
authors.lastname: Dardalhon
authors.forename: Slobodan
authors.initials: S
authors.lastname: Culina
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Gdoura
authors.forename: Peter
authors.initials: P
authors.lastname: van Endert
authors.forename: Stefania
authors.initials: S
authors.lastname: Francesconi
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004229:Dithiothreitol / Q000494:pharmacology; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D017353:Gene Deletion; D005816:Genetic Complementation Test; D016681:Genome, Fungal / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000378:metabolism; D007339:Insulysin / Q000737:chemistry* / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000201:enzymology* / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D007328:Insulin; D046912:Multiprotein Complexes; D029702:Schizosaccharomyces pombe Proteins; D014415:Tunicamycin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D010450:Endopeptidases; C586075:Iph1 protein, S pombe; D007339:Insulysin; D004229:Dithiothreitol; D020123:Sirolimus