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

Cowart, L. Ashley; Shotwell, Matthew S.; Worley, Mitchell L.; Richards, Adam; Montefusco, David; Hannun, Yusuf A.; Lu, Xinghua

doi:10.1038/msb.2010.3

Cited by 49 publications

(45 citation statements)

References 39 publications

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“…Moreover, it is expected that bioinformatic approaches will also help in the quest to define lipid-specific functions. In such an approach, functions for yeast sphingoid base phosphates were elucidated by "deconvoluting" gene-based transcriptomic data to lipidbased regulation by simultaneously analyzing transcriptomic and lipidomic results (95). Another very recent approach helps visualize sphingolipidomic results and correlates those with functional changes in transcriptomic data on sphingolipid enzymes (96).…”

Section: Implications Of This Paradigm Shiftmentioning

confidence: 99%

Many Ceramides

Hannun

Obeid

2011

Journal of Biological Chemistry

519

503

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Intensive research over the past 2 decades has implicated ceramide in the regulation of several cell responses. However, emerging evidence points to dramatic complexities in ceramide metabolism and structure that defy the prevailing unifying hypothesis on ceramide function that is based on the understanding of ceramide as a single entity. Here, we develop the concept that "ceramide" constitutes a family of closely related molecules, subject to metabolism by >28 enzymes and with >200 structurally distinct mammalian ceramides distinguished by specific structural modifications. These ceramides are synthesized in a combinatorial fashion with distinct enzymes responsible for the specific modifications. These multiple pathways of ceramide generation led to the hypothesis that individual ceramide molecular species are regulated by specific biochemical pathways in distinct subcellular compartments and execute distinct functions. In this minireview, we describe the "many ceramides" paradigm, along with the rationale, supporting evidence, and implications for our understanding of bioactive sphingolipids and approaches for unraveling these pathways.

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Section: Implications Of This Paradigm Shiftmentioning

confidence: 99%

Many Ceramides

Hannun

Obeid

2011

Journal of Biological Chemistry

519

503

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“…Recently, intracellular functions of sphingosine 1 phosphate in vertebrates have been revealed in control of protein ubiquitination (Alvarez et al 2010) and transcription (Hait et al 2009). In yeast, recent studies integrating genomic, transcriptomic, and lipidomic data have revealed a role for phytosphinganine 1 phosphate in regulating genes involved in mitochondrial respiration (Cowart et al 2010). Another sphingolipid connection to mitochondrial function comes from the dual localization of the yeast sphingomyelinase homolog, Isc1p, which is found in both ER and mitochondria (Vaena de Avalos et al 2004).…”

Section: Genetic Approaches To Sterol and Sphingolipid Functionmentioning

confidence: 99%

“…For the GPI-anchored proteins this could be because of the fact that most GPI-anchored proteins are remodeled to contain ceramide (Reggiori et al 1997) and that this step is required for their concentration into ER exit sites ). Sphingolipids also play roles in regulation of translation affecting formation of RNA processing bodies (Cowart et al 2010) and regulating translation initiation during the heat shock response (Meier et al 2006).…”

Section: Genetic Approaches To Sterol and Sphingolipid Functionmentioning

confidence: 99%

Distribution and Functions of Sterols and Sphingolipids

Hannich

Umebayashi²,

Riezman

2011

Cold Spring Harbor Perspectives in Biology

156

123

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Sterols and sphingolipids are considered mainly eukaryotic lipids even though both are present in some prokaryotes, with sphingolipids being more widespread than sterols. Both sterols and sphingolipids differ in their structural features in vertebrates, plants, and fungi. Interestingly, some invertebrates cannot synthesize sterols de novo and seem to have a reduced dependence on sterols. Sphingolipids and sterols are found in the plasma membrane, but we do not have a clear picture of their precise intracellular localization. Advances in lipidomics and subcellular fractionation should help to improve this situation. Genetic approaches have provided insights into the diversity of sterol and sphingolipid functions in eukaryotes providing evidence that these two lipid classes function together. Intermediates in sphingolipid biosynthesis and degradation are involved in signaling pathways, whereas sterol structures are converted to hormones. Both lipids have been implicated in regulating membrane trafficking.

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“…The lcb4⌬,lcb5⌬ double deletion strain, deleted in both sphingoid base kinases LCB4 and LCB5, showed up-regulation that was not significantly different from wild type, implying that the sphingoid base phosphates are not required for mediating CHA1 expression. This is a relevant conclusion because previous work has implicated PHS-1-phosphate in up-regulation of specific genes during heat stress (4,22,23) and therefore distinguishes DHS/PHS versus PHS-1-phosphate-regulated pathways. The lag1⌬ and lac1⌬ strains deleted in the ceramide synthases showed normal up-regulation, disfavoring the possibility that ceramide synthesis is required for CHA1 up-regulation.…”

mentioning

confidence: 68%

“…In particular, several responses to heat stress have been shown to require de novo synthesis of sphingolipids, and these include cell cycle arrest, proteolysis, and nutrient import (1)(2)(3)(4)(5)(6).…”

mentioning

confidence: 99%

Sphingoid Bases and the Serine Catabolic Enzyme CHA1 Define a Novel Feedforward/Feedback Mechanism in the Response to Serine Availability

Montefusco

Newcomb²,

Gandy³

et al. 2012

Journal of Biological Chemistry

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Background:The serine deaminase CHA1 responds to heat stress in a sphingolipid-dependent manner. Results: CHA1 requires de novo sphingoid base production for induction by serine, limiting growth-suppressing accumulation of sphingoid bases. Conclusion: Sphingoid bases are feedback sensors of serine availability, forming a feedforward/feedback loop through CHA1. Significance: This study defines a fundamental connection between sphingolipid and amino acid metabolic pathways with implications for disease.Targets of bioactive sphingolipids in Saccharomyces cerevisiae were previously identified using microarray experiments focused on sphingolipid-dependent responses to heat stress. One of these heat-induced genes is the serine deamidase/dehydratase Cha1 known to be regulated by increased serine availability. This study investigated the hypothesis that sphingolipids may mediate the induction of Cha1 in response to serine availability. The results showed that inhibition of de novo synthesis of sphingolipids, pharmacologically or genetically, prevented the induction of Cha1 in response to increased serine availability. Additional studies implicated the sphingoid bases phytosphingosine and dihydrosphingosine as the likely mediators of Cha1 up-regulation. The yeast protein kinases Pkh1 and Pkh2, known sphingoid base effectors, were found to mediate CHA1 up-regulation via the transcription factor Cha4. Because the results disclosed a role for sphingolipids in negative feedback regulation of serine metabolism, we investigated the effects of disrupting this mechanism on sphingolipid levels and on cell growth. Intriguingly, exposure of the cha1⌬ strain to high serine resulted in hyperaccumulation of endogenous serine and in turn a significant accumulation of sphingoid bases and ceramides. Under these conditions, the cha1⌬ strain displayed a significant growth defect that was sphingolipid-dependent. Together, this work reveals a feedforward/feedback loop whereby the sphingoid bases serve as sensors of serine availability and mediate up-regulation of Cha1 in response to serine availability, which in turn regulates sphingolipid levels by limiting serine accumulation.Sphingolipids constitute a unique class of lipids that have been implicated in a variety of functions in yeast, including nutrient uptake and cell cycle regulation. In particular, several responses to heat stress have been shown to require de novo synthesis of sphingolipids, and these include cell cycle arrest, proteolysis, and nutrient import (1-6).Microarray analysis analyzing the effects of heat stress on gene expression in the lcb1-100 strain, defective in de novo synthesis, was previously used to define genes whose regulation depended on de novo synthesis of sphingolipids (7). An especially intriguing gene among these is CHA1, which encodes a serine deamidase/dehydratase, known to be up-regulated by exogenous serine (8,9). This was of great interest because the enzyme serves to attenuate serine levels and because serine also serves as a limiting substrate in the ...

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

Abstract: Perturbing metabolic systems of bioactive sphingolipids with genetic approachMultiple types of “omics” data collected from the systemSystems approach for integrating multiple “omics” informationPredicting signal transduction information flow: lipid; TF activation; gene expression

Cited by 49 publications

References 39 publications

Many Ceramides

Many Ceramides

Distribution and Functions of Sterols and Sphingolipids

Sphingoid Bases and the Serine Catabolic Enzyme CHA1 Define a Novel Feedforward/Feedback Mechanism in the Response to Serine Availability

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