期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 22, 页码 E2271-E2280出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1318262111
关键词
mediator complex; MED15; cardiolipin; C. elegans
资金
- University of British Columbia (UBC)
- Child and Family Research Institute (CFRI)
- National Institutes of Health (NIH) [R01 DK074114]
- Canadian Institutes of Health Research [MOP-93713]
- Natural Sciences and Engineering Research Council of Canada [RGPIN 386398-13]
- Canada Foundation for Innovation
- UBC
- Center for Molecular Medicine and Therapeutics
- CFRI
- Deutsche Forschungsgemeinschaft (Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases Grants) [FOR885, SFB635, KFO286]
- Deutsche Forschungsgemeinschaft (Deutsch-Israelische Projektkooperation DIP8 Grant) [2014376]
- NIH Office of Research Infrastructure Programs [P40 OD010440]
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 (UPRER). 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 UPRER 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 UPRER genes, which cause protein misfolding. Therefore, the constitutively activated UPRER 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 UPRER is induced directly upon membrane disequilibrium and thus monitors altered ER homeostasis.
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