Lipid partitioning at the nuclear envelope controls membrane biogenesis.
Partitioning of lipid precursors between membranes and storage is crucial for cell growth, and its disruption underlies pathologies such as cancer, obesity, and type 2 diabetes. However, the mechanisms and signals that regulate this process are largely unknown. In yeast, lipid precursors are mainly used for phospholipid synthesis in nutrient-rich conditions in order to sustain rapid proliferation but are redirected to triacylglycerol (TAG) stored in lipid droplets during starvation. Here we investigate how cells reprogram lipid metabolism in the endoplasmic reticulum. We show that the conserved phosphatidate (PA) phosphatase Pah1, which generates diacylglycerol from PA, targets a nuclear membrane subdomain that is in contact with growing lipid droplets and mediates TAG synthesis. We find that cytosol acidification activates the master regulator of Pah1, the Nem1-Spo7 complex, thus linking Pah1 activity to cellular metabolic status. In the absence of TAG storage capacity, Pah1 still binds the nuclear membrane, but lipid precursors are redirected toward phospholipids, resulting in nuclear deformation and a proliferation of endoplasmic reticulum membrane. We propose that, in response to growth signals, activation of Pah1 at the nuclear envelope acts as a switch to control the balance between membrane biogenesis and lipid storage.
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
Antonio Daniel
AD
Barbosa
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
Hiroshi
H
Sembongi
Department of Food Science and the Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, NJ 08901.
Wen-Min
WM
Su
Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713 A Groningen, Netherlands.
Susana
S
Abreu
Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713 A Groningen, Netherlands.
Fulvio
F
Reggiori
Department of Food Science and the Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, NJ 08901.
George M
GM
Carman
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom ss560@cam.ac.uk.
Symeon
S
Siniossoglou
D004721:Endoplasmic Reticulum / Q000378:metabolism; D066292:Lipid Droplets / Q000378:metabolism*; D050356:Lipid Metabolism; D008563:Membrane Lipids / Q000378:metabolism*; D008566:Membranes / Q000378:metabolism; D009685:Nuclear Envelope / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010711:Phosphatidate Phosphatase / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D008563:Membrane Lipids; D009687:Nuclear Proteins; D010743:Phospholipids; D029701:Saccharomyces cerevisiae Proteins; D014280:Triglycerides; C079831:PAH1 protein, S cerevisiae; D010711:Phosphatidate Phosphatase