Journal article
Activation of the endoplasmic reticulum unfolded protein response by lipid disequilibrium without disturbed proteostasis in vivo
Proceedings of the National Academy of Sciences - PNAS, Vol.111(22), pp.E2271-E2280
06/03/2014
Handle:
https://hdl.handle.net/2376/104390
PMCID: PMC4050548
PMID: 24843123
Abstract
The Mediator is a conserved transcriptional coregulator complex required for eukaryotic gene expression. In Caenorhabditis elegans, the Mediator subunit mdt-15 is essential for the expression of genes involved in fatty acid metabolism and ingestion-associated stress responses. mdt-15 loss of function causes defects in reproduction and mobility and shortens lifespan. In the present study, we find that worms with mutated or depleted mdt-15 (mdt-15 worms) exhibit decreased membrane phospholipid desaturation, especially in phosphatidylcholine. Accordingly, mdt-15 worms exhibit disturbed endoplasmic reticulum (ER) homeostasis, as indicated by a constitutively activated ER unfolded protein response (UPR(ER)). Activation of this stress response is only partially the consequence of reduced membrane lipid desaturation, implicating other mdt-15-regulated processes in maintaining ER homeostasis. Interestingly, mdt-15 inactivation or depletion of the lipid metabolism enzymes stearoyl-CoA-desaturases (SCD) and S-adenosyl methionine synthetase (sams-1) activates the UPR(ER) without promoting misfolded protein aggregates. Moreover, these worms exhibit wild-type sensitivity to chemically induced protein misfolding, and they do not display synthetic lethality with mutations in UPR(ER) genes, which cause protein misfolding. Therefore, the constitutively activated UPR(ER) in mdt-15, SCD, and sams-1 worms is not the consequence of proteotoxic stress but likely is the direct result of changes in ER membrane fluidity and composition. Together, our data suggest that the UPR(ER) is induced directly upon membrane disequilibrium and thus monitors altered ER homeostasis.
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Details
- Title
- Activation of the endoplasmic reticulum unfolded protein response by lipid disequilibrium without disturbed proteostasis in vivo
- Creators
- Nicole S Hou - Centre for Molecular Medicine and Therapeutics andChild and Family Research Institute, Vancouver, BC, Canada V5Z 4H4;Graduate Program in Cell and Developmental Biology andAljona Gutschmidt - Institute for Genetics andCologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany; andDaniel Y Choi - Centre for Molecular Medicine and Therapeutics andChild and Family Research Institute, Vancouver, BC, Canada V5Z 4H4Keouna Pather - Centre for Molecular Medicine and Therapeutics andChild and Family Research Institute, Vancouver, BC, Canada V5Z 4H4Xun Shi - School of Molecular Biosciences, Washington State University, Pullman, WA 99164Jennifer L Watts - School of Molecular Biosciences, Washington State University, Pullman, WA 99164Thorsten Hoppe - Institute for Genetics andCologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany; andStefan Taubert - Centre for Molecular Medicine and Therapeutics andChild and Family Research Institute, Vancouver, BC, Canada V5Z 4H4;Graduate Program in Cell and Developmental Biology andDepartment of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V5Z 4H4; taubert@cmmt.ubc.ca
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.111(22), pp.E2271-E2280
- Academic Unit
- Molecular Biosciences, School of
- Publisher
- United States
- Grant note
- MOP-93713 / Canadian Institutes of Health Research R01 DK074114 / NIDDK NIH HHS P40 OD010440 / NIH HHS R01-DK074114 / NIDDK NIH HHS
- Identifiers
- 99900546510201842
- Language
- English
- Resource Type
- Journal article