title: The FOXO transcription factor DAF-16 bypasses ire-1 requirement to promote endoplasmic reticulum homeostasis.
abstract: The unfolded protein response (UPR) allows cells to adjust the capacity of the endoplasmic reticulum (ER) to the load of ER-associated tasks. We show that activation of the Caenorhabditis elegans transcription factor DAF-16 and its human homolog FOXO3 restore secretory protein metabolism when the UPR is dysfunctional.We show that DAF-16 establishes alternative ER-associated degradation systems that degrade misfolded proteins independently of the ER stress sensor ire-1 and the ER-associated E3 ubiquitin ligase complex sel-11/sel-1. This is achieved by enabling autophagy-mediated degradation and by increasing the levels of skr-5, a component of an ER associated ubiquitin ligase complex. These degradation systems can act together with the conserved UPR to improve ER homeostasis and ER stress resistance, beyond wild-type levels. Because there is no sensor in the ER that activates DAF-16 in response to intrinsic ER stress, natural or artificial interventions that activate DAF-16 may be useful therapeutic approaches to maintain ER homeostasis.
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, 5290002 Ramat Gan, Israel.
authors.forename: Modi
authors.initials: M
authors.lastname: Safra
authors.affiliation: Experimental Physics I, University of Bayreuth, 95440 Bayreuth, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Fickentscher
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, 5290002 Ramat Gan, Israel.
authors.forename: Mor
authors.initials: M
authors.lastname: Levi-Ferber
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, 5290002 Ramat Gan, Israel.
authors.forename: Yehuda M
authors.initials: YM
authors.lastname: Danino
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, 5290002 Ramat Gan, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Haviv-Chesner
authors.affiliation: Program of Development, Aging and Regeneration, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Malene
authors.initials: M
authors.lastname: Hansen
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, 5290002 Ramat Gan, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Juven-Gershon
authors.affiliation: Experimental Physics I, University of Bayreuth, 95440 Bayreuth, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Weiss
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, 5290002 Ramat Gan, Israel. Electronic address: sivan.korenblit@biu.ac.il.
authors.forename: Sivan
authors.initials: S
authors.lastname: Henis-Korenblit
mesh_terms: D000818:Animals; D001343:Autophagy; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D060746:Endoplasmic Reticulum-Associated Degradation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D029742:Caenorhabditis elegans Proteins; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C108831:daf-16 protein, C elegans; D017346:Protein Serine-Threonine Kinases; C541905:IRE-1 protein, C elegans