The FOXO transcription factor DAF-16 bypasses ire-1 requirement to promote endoplasmic reticulum homeostasis

Modi Safra, Rolf Fickentscher, Mor Levi-Ferber, Yehuda M. Danino, Anat Haviv-Chesner, Malene Hansen, Tamar Juven-Gershon, Matthias Weiss, Sivan Henis-Korenblit

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish
Pages (from-to)870-881
Number of pages12
JournalCell Metabolism
Volume20
Issue number5
DOIs
StatePublished - 4 Nov 2014

Bibliographical note

Publisher Copyright:
© 2014 Elsevier Inc.

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