title: Prolonged starvation drives reversible sequestration of lipid biosynthetic enzymes and organelle reorganization in Saccharomyces cerevisiae.
abstract: Cells adapt to changing nutrient availability by modulating a variety of processes, including the spatial sequestration of enzymes, the physiological significance of which remains controversial. These enzyme deposits are claimed to represent aggregates of misfolded proteins, protein storage, or complexes with superior enzymatic activity. We monitored spatial distribution of lipid biosynthetic enzymes upon glucose depletion in Saccharomyces cerevisiae. Several different cytosolic-, endoplasmic reticulum-, and mitochondria-localized lipid biosynthetic enzymes sequester into distinct foci. Using the key enzyme fatty acid synthetase (FAS) as a model, we show that FAS foci represent active enzyme assemblies. Upon starvation, phospholipid synthesis remains active, although with some alterations, implying that other foci-forming lipid biosynthetic enzymes might retain activity as well. Thus sequestration may restrict enzymes' access to one another and their substrates, modulating metabolic flux. Enzyme sequestrations coincide with reversible drastic mitochondrial reorganization and concomitant loss of endoplasmic reticulum-mitochondria encounter structures and vacuole and mitochondria patch organelle contact sites that are reflected in qualitative and quantitative changes in phospholipid profiles. This highlights a novel mechanism that regulates lipid homeostasis without profoundly affecting the activity status of involved enzymes such that, upon entry into favorable growth conditions, cells can quickly alter lipid flux by relocalizing their enzymes.
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH) and German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, D-69120 Heidelberg, Germany.
authors.forename: Harsha Garadi
authors.initials: HG
authors.lastname: Suresh
authors.affiliation: NCCR Chemical Biology, Department of Biochemistry, University of Geneva, CH-1211 Geneva, Switzerland.
authors.forename: Aline Xavier
authors.initials: AX
authors.lastname: da Silveira Dos Santos
authors.affiliation: Structural and Computational Biology Unit and Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, D-69117 Heidelberg, Germany Structural and Computational Biology Unit and Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, D-69117 Heidelberg, Germany.
authors.forename: Wanda
authors.initials: W
authors.lastname: Kukulski
authors.affiliation: Department of Medicine I and Clinical Chemistry, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Tyedmers
authors.affiliation: NCCR Chemical Biology, Department of Biochemistry, University of Geneva, CH-1211 Geneva, Switzerland.
authors.forename: Howard
authors.initials: H
authors.lastname: Riezman
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH) and German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, D-69120 Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Bukau
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH) and German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, D-69120 Heidelberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Mogk
mesh_terms: D000222:Adaptation, Physiological; D053898:Biosynthetic Pathways; D003470:Culture Media; D004721:Endoplasmic Reticulum / Q000502:physiology* / Q000648:ultrastructure; D064429:Fatty Acid Synthases / Q000378:metabolism*; D050155:Lipogenesis; D050296:Microbial Viability; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D021381:Protein Transport; D006180:Proton-Translocating ATPases / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D017855:Transferases (Other Substituted Phosphate Groups) / Q000378:metabolism
chemical_list: D003470:Culture Media; D029701:Saccharomyces cerevisiae Proteins; D064429:Fatty Acid Synthases; D017855:Transferases (Other Substituted Phosphate Groups); C478389:PIS1 protein, S cerevisiae; C092477:PMA1 protein, S cerevisiae; D006180:Proton-Translocating ATPases; C526685:FAS1 protein, S cerevisiae; C577477:FAS2 protein, S cerevisiae