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Cell Metab. 2014 Nov 4;20(5):870-881. doi: 10.1016/j.cmet.2014.09.006.

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

Author information

1
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, 5290002 Ramat Gan, Israel.
2
Experimental Physics I, University of Bayreuth, 95440 Bayreuth, Germany.
3
Program of Development, Aging and Regeneration, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
4
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, 5290002 Ramat Gan, Israel. Electronic address: sivan.korenblit@biu.ac.il.

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.

PMID:
25448701
DOI:
10.1016/j.cmet.2014.09.006
[Indexed for MEDLINE]
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