title: Distinct signaling roles of ceramide species in yeast revealed through systematic perturbation and systems biology analyses.
abstract: Ceramide, the central molecule of sphingolipid metabolism, is an important bioactive molecule that participates in various cellular regulatory events and that has been implicated in disease. Deciphering ceramide signaling is challenging because multiple ceramide species exist, and many of them may have distinct functions. We applied systems biology and molecular approaches to perturb ceramide metabolism in the yeast Saccharomyces cerevisiae and inferred causal relationships between ceramide species and their potential targets by combining lipidomic, genomic, and transcriptomic analyses. We found that during heat stress, distinct metabolic mechanisms controlled the abundance of different groups of ceramide species and provided experimental support for the importance of the dihydroceramidase Ydc1 in mediating the decrease in dihydroceramides during heat stress. Additionally, distinct groups of ceramide species, with different N-acyl chains and hydroxylations, regulated different sets of functionally related genes, indicating that the structural complexity of these lipids produces functional diversity. The transcriptional modules that we identified provide a resource to begin to dissect the specific functions of ceramides.
authors.affiliation: 1Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29445, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Montefusco
authors.forename: Lujia
authors.initials: L
authors.lastname: Chen
authors.forename: Nabil
authors.initials: N
authors.lastname: Matmati
authors.forename: Songjian
authors.initials: S
authors.lastname: Lu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Newcomb
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Cooper
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.forename: Xinghua
authors.initials: X
authors.lastname: Lu
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D055572:Ceramidases / Q000235:genetics / Q000378:metabolism; D002518:Ceramides / Q000737:chemistry / Q000378:metabolism*; D016000:Cluster Analysis; D015966:Gene Expression Regulation, Fungal; D063990:Gene Ontology; D006358:Hot Temperature; D050356:Lipid Metabolism / Q000235:genetics; D015394:Molecular Structure; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013107:Sphingolipids / Q000737:chemistry / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics; D049490:Systems Biology / Q000379:methods*; D059467:Transcriptome / Q000235:genetics
chemical_list: D002518:Ceramides; D029701:Saccharomyces cerevisiae Proteins; D013107:Sphingolipids; C109343:dihydroceramide; D000581:Amidohydrolases; C000588734:alkaline dihydroceramidase, S cerevisiae; D055572:Ceramidases