Revealing a signaling role of phytosphingosine‐1‐phosphate in yeast

• Published in: Molecular systems biology 2010, Vol.6 (1), p.349-n/a
• Main Authors: Cowart, L Ashley, Shotwell, Matthew, Worley, Mitchell L, Richards, Adam J, Montefusco, David J, Hannun, Yusuf A, Lu, Xinghua
• Format: Article
• Language: English
• Subjects: Bayes Theorem; Cell cycle; Ceramide; Cluster Analysis; Design of experiments; EMBO09; EMBO37; Experimental design; Experiments; Gene expression; Hybridization; information integration; Information processing; Kinases; Lipid Metabolism; lipidomics; Lipids; Metabolic Networks and Pathways; Metabolism; Metabolites; Mitochondria; Mutation; Phosphates; Saccharomyces cerevisiae - chemistry; Saccharomyces cerevisiae - enzymology; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Signal Transduction; Signaling; Sphingolipids; Sphingolipids - metabolism; Sphingosine - analogs & derivatives; Sphingosine - genetics; Sphingosine - metabolism; Stress response; Systems Biology - methods; Transcription Factors; transcriptomics; Yeast; Yeasts
• ISSN: 1744-4292; 1744-4292
• DOI: 10.1038/msb.2010.3

Sphingolipids including sphingosine‐1‐phosphate and ceramide participate in numerous cell programs through signaling mechanisms. This class of lipids has important functions in stress responses; however, determining which sphingolipid mediates specific events has remained encumbered by the numerous metabolic interconnections of sphingolipids, such that modulating a specific lipid of interest through manipulating metabolic enzymes causes ‘ripple effects’, which change levels of many other lipids. Here, we develop a method of integrative analysis for genomic, transcriptomic, and lipidomic data to address this previously intractable problem. This method revealed a specific signaling role for phytosphingosine‐1‐phosphate, a lipid with no previously defined specific function in yeast, in regulating genes required for mitochondrial respiration through the HAP complex transcription factor. This approach could be applied to extract meaningful biological information from a similar experimental design that produces multiple sets of high‐throughput data. Synopsis In contemporary biomedical research, gene mutation remains the most powerful and commonly used tool in molecular and systems biology for perturbation and dissection of biological systems. However, as biological systems consist of highly connected networks, for example, metabolic networks or signal transduction networks, perturbing one portion could result in widely spread effects across the network. Such ‘ripple effects’ in systems pose a challenge to the paradigm of investigating the role of a metabolite through mutating enzymes required for its production. In this study, we have developed a systems biology approach that integrates different types of ‘‐omics’ data to identify signal transduction pathways involving spingolipids and gene expression. See Figure 1 for an overall scheme of our approaches. Sphingolipids are a family of bioactive lipids that have important signaling functions in cells; in yeast, de novo synthesis is required to mediate the cell response to heat shock. We hypothesized that a specific sphingolipid, phyto‐sphingosine‐1‐phosphate (PHS1P), functions as a signaling molecule in the heat stress response (HSR) because, though its mammalian counterparts are known to have important signaling roles, the function of this metabolite in yeast remains unknown. To identify a putative role of PHS1P in the HSR, we deleted the genes involved in production (LCB4 and LCB5) and degradation (DPL1) of PHS