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 language | English |
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Pages (from-to) | 870-881 |
Number of pages | 12 |
Journal | Cell Metabolism |
Volume | 20 |
Issue number | 5 |
DOIs | |
State | Published - 4 Nov 2014 |
Bibliographical note
Publisher Copyright:© 2014 Elsevier Inc.
Funding
We thank Cynthia Kenyon for helpful discussions and support. This study was initiated in the Kenyon lab, where it was supported by NIH grant R37 AG011816 to Cynthia Kenyon, and subsequently by a United States-Israel Binational Science Foundation to S.H.-K. and Cynthia Kenyon (grant 2009356), by an Israel Science Foundation grant to S.H.-K. (1749/11), by a Marie Curie International Reintegration Grant to S.H.-K. (grant 256551), and by grant no. I-1211-309.13/2012 from the German-Israeli Foundation for Scientific Research and Development to S.H.-K. and M.W. Some nematode strains were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources and by Dr. Shohei Mitani, National Bioresource Project for the nematode, Tokyo Women’s Medical University School of Medicine, Japan. We thank Prof. Peter Naredi (Umea University, Sweden) for the DAF-28::GFP expressing strain and Dr. Jeremy Don and his lab members (Bar-Ilan University, Israel) for help with cell culture.
Funders | Funder number |
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Cynthia Kenyon | 2009356 |
Tokyo Women’s Medical University School of Medicine, Japan | |
National Institutes of Health | R37 AG011816 |
German-Israeli Foundation for Scientific Research and Development | |
United States-Israel Binational Science Foundation | |
Israel Science Foundation | 256551, I-1211-309.13/2012 |