Activation of the endoplasmic reticulum unfolded protein response by lipid disequilibrium without disturbed proteostasis in vivo.
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.
Centre for Molecular Medicine and Therapeutics andChild and Family Research Institute, Vancouver, BC, Canada V5Z 4H4;Graduate Program in Cell and Developmental Biology and.
Nicole S
NS
Hou
Institute for Genetics andCologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany; and.
Aljona
A
Gutschmidt
Centre for Molecular Medicine and Therapeutics andChild and Family Research Institute, Vancouver, BC, Canada V5Z 4H4;
Daniel Y
DY
Choi
Centre for Molecular Medicine and Therapeutics andChild and Family Research Institute, Vancouver, BC, Canada V5Z 4H4;
Keouna
K
Pather
School of Molecular Biosciences, Washington State University, Pullman, WA 99164.
Xun
X
Shi
School of Molecular Biosciences, Washington State University, Pullman, WA 99164.
Jennifer L
JL
Watts
Institute for Genetics andCologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany; and.
Thorsten
T
Hoppe
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.
Stefan
S
Taubert
D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002308:Cardiolipins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D008055:Lipids / Q000096:biosynthesis; D008928:Mitochondria / Q000378:metabolism; D010713:Phosphatidylcholines / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D057165:Proteostasis Deficiencies / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000502:physiology*
C513281:ARC105 protein, C elegans; D000214:Acyl Coenzyme A; D029742:Caenorhabditis elegans Proteins; D002308:Cardiolipins; D005227:Fatty Acids; D008055:Lipids; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D014157:Transcription Factors; C017725:stearoyl-coenzyme A; C483858:phosphatidylethanolamine
C. elegans; MED15; cardiolipin; mediator complex