title: The protein kinase Sch9 is a key regulator of sphingolipid metabolism in Saccharomyces cerevisiae.
abstract: The Saccharomyces cerevisiae protein kinase Sch9 is an in vitro and in vivo effector of sphingolipid signaling. This study examines the link between Sch9 and sphingolipid metabolism in S. cerevisiae in vivo based on the observation that the sch9Δ mutant displays altered sensitivity to different inhibitors of sphingolipid metabolism, namely myriocin and aureobasidin A. Sphingolipid profiling indicates that sch9Δ cells have increased levels of long-chain bases and long-chain base-1 phosphates, decreased levels of several species of (phyto)ceramides, and altered ratios of complex sphingolipids. We show that the target of rapamycin complex 1-Sch9 signaling pathway functions to repress the expression of the ceramidase genes YDC1 and YPC1, thereby revealing, for the first time in yeast, a nutrient-dependent transcriptional mechanism involved in the regulation of sphingolipid metabolism. In addition, we establish that Sch9 affects the activity of the inositol phosphosphingolipid phospholipase C, Isc1, which is required for ceramide production by hydrolysis of complex sphingolipids. Given that sphingolipid metabolites play a crucial role in the regulation of stress tolerance and longevity of yeast cells, our data provide a model in which Sch9 regulates the latter phenotypes by acting not only as an effector but also as a regulator of sphingolipid metabolism.
authors.affiliation: Functional Biology, KU Leuven, 3001 Heverlee, Belgium Centre for Surface Chemistry and Catalysis, KU Leuven, 3001 Heverlee, Belgium Centre of Microbial and Plant Genetics, KU Leuven, 3001 Heverlee, Belgium Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29403.
authors.forename: Erwin
authors.initials: E
authors.lastname: Swinnen
authors.forename: Tobias
authors.initials: T
authors.lastname: Wilms
authors.forename: Jolanta
authors.initials: J
authors.lastname: Idkowiak-Baldys
authors.forename: Bart
authors.initials: B
authors.lastname: Smets
authors.forename: Pepijn
authors.initials: P
authors.lastname: De Snijder
authors.forename: Sabina
authors.initials: S
authors.lastname: Accardo
authors.forename: Ruben
authors.initials: R
authors.lastname: Ghillebert
authors.forename: Karin
authors.initials: K
authors.lastname: Thevissen
authors.forename: Bruno
authors.initials: B
authors.lastname: Cammue
authors.forename: Dirk
authors.initials: D
authors.lastname: De Vos
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.forename: Joris
authors.initials: J
authors.lastname: Winderickx
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology; D002518:Ceramides / Q000096:biosynthesis*; D047630:Depsipeptides / Q000494:pharmacology; D025141:Drug Resistance, Fungal; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D015966:Gene Expression Regulation, Fungal; D055786:Gene Knockout Techniques; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014158:Transcription, Genetic; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D002518:Ceramides; D047630:Depsipeptides; D005229:Fatty Acids, Monounsaturated; D029701:Saccharomyces cerevisiae Proteins; D013107:Sphingolipids; C071398:aureobasidin A; D017346:Protein Serine-Threonine Kinases; C530964:SCH9 protein, S cerevisiae; C419391:ISC1 protein, S cerevisiae; D010738:Type C Phospholipases; C012491:phytosphingosine; D013110:Sphingosine; C001996:thermozymocidin