The FOXO Transcription Factor DAF-16 Bypasses ire-1 Requirement to Promote Endoplasmic Reticulum Homeostasis

• Published in: Cell metabolism 2014-11, Vol.20 (5), p.870-881
• Main Authors: Safra, Modi, Fickentscher, Rolf, Levi-Ferber, Mor, Danino, Yehuda M., Haviv-Chesner, Anat, Hansen, Malene, Juven-Gershon, Tamar, Weiss, Matthias, Henis-Korenblit, Sivan
• Format: Article
• Language: English
• Subjects: Animals; Autophagy; Caenorhabditis elegans - cytology; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Endoplasmic Reticulum Stress; Endoplasmic Reticulum-Associated Degradation; Forkhead Box Protein O3; Forkhead Transcription Factors - metabolism; HEK293 Cells; Humans; Mutation; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Unfolded Protein Response
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2014.09.006

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. [Display omitted] •DAF-16 activation bypasses ire-1 requirement for ER homeostasis and function•Activated FOXO3 bypasses IRE1 requirement for secretory trafficking in human cells•Activated DAF-16 enables autophagy-mediated ERAD alongside proteasome-mediated ERAD•Environmental stresses can activate the DAF-16-mediated ER homeostasis pathway Safra et al. elucidate the mechanism by which reducing insulin/IGF-1 signaling improves ER homeostasis and show that this improvement is achieved independently of the ER stress sensor IRE-1 by facilitating the degradation of misfolded secretory proteins from the ER via alternate autophagy- and proteasome-mediated ERAD pathways.