Activation of the endoplasmic reticulum unfolded protein response by lipid disequilibrium without disturbed proteostasis in vivo
Autor: | Aljona Gutschmidt, Daniel Y. Choi, Thorsten Hoppe, Stefan Taubert, Keouna Pather, Jennifer L. Watts, Nicole S. Hou, Xun Shi |
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Rok vydání: | 2014 |
Předmět: |
Cardiolipins
Protein subunit Protein aggregation Mitochondrion Biology Endoplasmic Reticulum chemistry.chemical_compound Cardiolipin Animals Homeostasis Proteostasis Deficiencies Caenorhabditis elegans Caenorhabditis elegans Proteins Multidisciplinary Endoplasmic reticulum Phosphatidylethanolamines Fatty Acids Lipid metabolism Lipids Cell biology Mitochondria Proteostasis chemistry PNAS Plus Unfolded protein response Phosphatidylcholines Unfolded Protein Response Acyl Coenzyme A Transcription Factors |
Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 111(22) |
ISSN: | 1091-6490 |
Popis: | 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. |
Databáze: | OpenAIRE |
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