Biosynthesis and Trafficking of Sphingolipids in the Yeast <i>Saccharomyces cerevisiae</i>

Funato, Koichi; Vallée, Béatrice; Riezman, Howard

doi:10.1021/bi026616d

Cited by 66 publications

(70 citation statements)

References 84 publications

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“…Ceramide levels are decreased in orm1Dorm2D cells (Han et al, 2010). Impaired de novo ceramide synthesis in orm1D orm2D cells is supported by accumulation of very long fatty acid levels [ceramide is made by linkage of long chain base with very long chain fatty acyl CoA (Funato et al, 2002)]. We now report physical interaction of Orm1 and Orm2 with the ceramide synthase subunit, Lac1 (Fig.…”

Section: Discussionmentioning

confidence: 61%

“…The ORMDL proteins regulate sphingolipid synthesis by physically associating with serine palmitoyltransferase (SPT), which catalyzes the first and rate-limiting step of sphingolipid synthesis. SPT mediates production of long chain bases from the condensation of serine and palmitoyl CoA (Funato et al, 2002). Ceramide is then generated upon addition of a second long chain fatty acid to a long chain base.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of sphingolipid synthesis via Orm1 and Orm2 in yeast

Liu

Huang

Polu

et al. 2012

Journal of Cell Science

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SummarySphingolipids are crucial components of membranes, and sphingolipid metabolites serve as signaling molecules. Yeast Orm1 and Orm2 belong to a conserved family of ER membrane proteins that regulate serine palmitoyltransferase, which catalyzes the first and ratelimiting step in sphingolipid synthesis. We now show that sphingolipid synthesis through Orm1 is a target of TOR signaling, which regulates cell growth in response to nutritional signals. Orm1 phosphorylation is dependent on the Tap42-phosphatase complex, which acts downstream of TOR protein kinase complex 1. In temperature-sensitive tap42-11 cells, impaired Orm1 phosphorylation occurs concomitantly with reduced sphingolipid synthesis. A second mechanism for regulating sphingolipid synthesis is through control of Orm2 protein level. The Orm2 protein level responds to ER stress conditions, increasing when cells are treated with tunicamycin or DTT, agents that induce the unfolded protein response (UPR). The sphingolipid intermediates (long chain base and ceramide) are decreased when ORM2 is overexpressed, suggesting that sphingolipid synthesis is repressed under ER stress conditions. Finally, in the absence of the Orms, the UPR is constitutively activated. Lipid dysregulation in the absence of the Orms might signal to the ER from the plasma membrane because UPR activation is dependent on a cell surface sensor and the mitogen-activated protein kinase (MAPK) cell wall integrity pathway. Thus, sphingolipid synthesis and the UPR are coordinately regulated.

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Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Regulation of sphingolipid synthesis via Orm1 and Orm2 in yeast

Liu

Huang

Polu

et al. 2012

Journal of Cell Science

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“…In eukaryotic cells, sphingolipids play important roles in normal cell membrane architecture, and protein trafficking and sorting (Funato et al, 2002;Gruenberg, 2001;Ikonen, 2001). Various sphingoid bases and their metabolites also act as second messengers in the heat-stress response, regulation of cell growth and cell cycle progression, and apoptosis (Dickson and Lester, 1999;Obeid et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Treatment with the SPT2 inhibitor myriocin, or mutation of the SPT1 subunit cause the GPI-linked protein Gas1p to accumulate in the ER. In yeast, ceramide-rich lipid rafts form in the ER, and disruption of these rafts is responsible for the reduced rate of transport of cholesterol and raftassociated proteins Gas1p, Pma1p and Nce2p from the ER to the cell surface (Bagnat et al, 2000;Bagnat and Simons, 2002;Funato et al, 2002;Perry, 2002). SPT1 temperature-sensitive mutants are deficient in receptor-mediated endocytosis (Zanolari et al, 2000), and downstream sphingoid bases, such as dihydrosphingosine (sphinganine), act as signaling molecules regulating endocytosis (Dickson and Lester, 1999).…”

Section: Introductionmentioning

confidence: 99%

Sphingolipid synthesis is necessary for kinetoplast segregation and cytokinesis in Trypanosoma brucei

Fridberg

Olson

Nakayasu

et al. 2008

Journal of Cell Science

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Sphingolipids and their metabolites have been thought crucial for cell growth and cell cycle progression, membrane and protein trafficking, signal transduction, and formation of lipid rafts; however, recent studies in trypanosomes point to the dispensability of sphingolipids in some of these processes. In this study, we explore the requirements for de novo sphingolipid biosynthesis in the insect life cycle stage of the African trypanosome Trypanosoma brucei by inhibiting the enzyme serine palmitoyltransferase (SPT2) by using RNA interference or treatment with a potent SPT2 inhibitor myriocin. Mass spectrometry revealed that upon SPT2 inhibition, the parasites contained substantially reduced levels of inositolphosphorylceramide. Although phosphatidylcholine and cholesterol levels were increased to compensate for this loss, the cells were ultimately not viable. The most striking result of sphingolipid reduction in procyclic T. brucei was aberrant cytokinesis, characterized by incomplete cleavage-furrow formation, delayed kinetoplast segregation and emergence of cells with abnormal DNA content. Organelle replication continued despite sphingolipid depletion, indicating that sphingolipids act as second messengers regulating cellular proliferation and completion of cytokinesis. Distention of the mitochondrial membrane, formation of multilamellar structures within the mitochondrion and near the nucleus, accumulation of lipid bodies and, less commonly, disruption of the Golgi complex were observed after prolonged sphingolipid depletion. These findings suggest that some aspects of vesicular trafficking may be compromised. However, flagellar membrane targeting and the association of the flagellar membrane protein calflagin with detergent-resistant membranes were not affected, indicating that the vesicular trafficking defects were mild. Our studies indicate that sphingolipid biosynthesis is vital for cell cycle progression and cell survival, but not essential for the normal trafficking of flagellar membrane-associated proteins or lipid raft formation in procyclic T. brucei.

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“…This review describes and integrates advances in understanding the sphingolipid metabolism and functions of S. cerevisiae during the past 2 years and focuses on the role of LCBs in signal transduction pathways that regulate growth, responses to stress, particularly heat stress, exocytosis of plasma membrane proteins, endocytosis, and actin cytoskeleton dynamics. Previous reviews should be consulted for topics that are not presented here and for more detailed coverage of areas only briefly touched upon in this review (8)(9)(10)(11)(12)(13)(14).…”

mentioning

confidence: 99%

Thematic Review Series: Sphingolipids. New insights into sphingolipid metabolism and function in budding yeast

Dickson

2008

Journal of Lipid Research

206

217

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Our understanding of sphingolipid metabolism and functions in the baker's yeast Saccharomyces cerevisiae has progressed substantially in the past 2 years. Yeast sphingolipids contain a C 26 -acyl moiety, all of the genes necessary to make these long-chain fatty acids have been identified, and a mechanism for how chain length is determined has been proposed. Advances in understanding how the de novo synthesis of ceramide and complex sphingolipids is regulated have been made, and they demonstrate that the Target Of Rapamycin Complex 2 (TORC2) controls ceramide synthase activity. Other work shows that TORC2 regulates the level of complex sphingolipids in a pathway using the Slm1 and Slm2 proteins to control the protein phosphatase calcineurin, which regulates the breakdown of complex sphingolipids. The activity of Slm1 and Slm2 has also been shown to be regulated during heat stress by phosphoinositides and TORC2, along with sphingoid long-chain bases and the Pkh1 and Pkh2 protein kinases, to control the actin cytoskeleton, the trafficking of nutrient transporters, and cell viability.Together, these results provide the first molecular insights into understanding previous genetic interaction data that indicated a connection between sphingolipids and the TORC2 and phosphoinositide signaling networks. This new knowledge provides a foundation for greatly advancing our understanding of sphingolipid biology in yeast.-Dickson, R. C. New insights into sphingolipid metabolism and function in budding yeast. J. Lipid Res. 2008. 49: 909-921.

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Biosynthesis and Trafficking of Sphingolipids in the Yeast Saccharomyces cerevisiae

Cited by 66 publications

References 84 publications

Regulation of sphingolipid synthesis via Orm1 and Orm2 in yeast

Regulation of sphingolipid synthesis via Orm1 and Orm2 in yeast

Sphingolipid synthesis is necessary for kinetoplast segregation and cytokinesis in Trypanosoma brucei

Thematic Review Series: Sphingolipids. New insights into sphingolipid metabolism and function in budding yeast

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