TORC1 inhibition induces lipid droplet replenishment in yeast

Mol Cell Biol. 2015 Feb;35(4):737-46. doi: 10.1128/MCB.01314-14. Epub 2014 Dec 15.

Abstract

Lipid droplets (LDs) are intracellular structures that regulate neutral lipid homeostasis. In mammals, LD synthesis is inhibited by rapamycin, a known inhibitor of the mTORC1 pathway. In Saccharomyces cerevisiae, LD dynamics are modulated by the growth phase; however, the regulatory pathways involved are unknown. Therefore, we decided to study the role of the TORC1 pathway on LD metabolism in S. cerevisiae. Interestingly, rapamycin treatment resulted in a fast LD replenishment and growth inhibition. The discovery that osmotic stress (1 M sorbitol) also induced LD synthesis but not growth inhibition suggested that the induction of LDs in yeast is not a secondary response to reduced growth. The induction of LDs by rapamycin was due to increased triacylglycerol but not sterol ester synthesis. Induction was dependent on the TOR downstream effectors, the PP2A-related phosphatase Sit4p and the regulatory protein Tap42p. The TORC1-controlled transcriptional activators Gln3p, Gat1p, Rtg1p, and Rtg3p, but not Msn2p and Msn4p, were required for full induction of LDs by rapamycin. Furthermore, we show that the deletion of Gln3p and Gat1p transcription factors, which are activated in response to nitrogen availability, led to abnormal LD dynamics. These results reveal that the TORC1 pathway is involved in neutral lipid homeostasis in yeast.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Cholesterol Esters / metabolism
  • GATA Transcription Factors / deficiency
  • GATA Transcription Factors / genetics
  • Gene Expression Regulation, Fungal*
  • Lipid Droplets / chemistry
  • Lipid Droplets / drug effects
  • Lipid Droplets / metabolism*
  • Lipid Metabolism / drug effects
  • Osmotic Pressure
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Signal Transduction
  • Sirolimus / pharmacology
  • Sorbitol / pharmacology
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / deficiency
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Triglycerides / biosynthesis

Substances

  • Adaptor Proteins, Signal Transducing
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Cholesterol Esters
  • GAT1 protein, S cerevisiae
  • GATA Transcription Factors
  • GLN3 protein, S cerevisiae
  • Phosphoinositide-3 Kinase Inhibitors
  • RTG1 protein, S cerevisiae
  • RTG3 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • TAP42 protein, S cerevisiae
  • TORC1 protein complex, S cerevisiae
  • Transcription Factors
  • Triglycerides
  • Sorbitol
  • TOR1 protein, S cerevisiae
  • Protein Phosphatase 2
  • SIT4 protein, S cerevisiae
  • Sirolimus