Identification of C18:1-Phytoceramide as the Candidate Lipid Mediator for Hydroxyurea Resistance in Yeast

Matmati, Nabil; Metelli, Alessandra; Tripathi, Kaushlendra; Yan, Shuqi; Mohanty, Bidyut K.; Hannun, Yusuf A.

doi:10.1074/jbc.m112.444802

Cited by 32 publications

(40 citation statements)

References 35 publications

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“…inactivation of Swe1 are dependent on sphingolipids. This is also consistent with a previous study that showed that the PP2A Cdc55 -Swe1 cascade is a downstream target of the sphingolipid, phytoceramide (59). We conclude that deletion of the regulatory subunit of PP2A Cdc55 makes the cells unresponsive to the availability of sphingolipids (SLs), which results in pertained activation of Swe1 and extension of the G1/S phase.…”

Section: Lipolysis-defective Mutants Accumulate Saturated and Unsatursupporting

confidence: 80%

Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression

Chauhan

Visram

Cristobal-Sarramian

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cell growth and division requires the precise duplication of cellular DNA content but also of membranes and organelles. Knowledge about the cell-cycle-dependent regulation of membrane and storage lipid homeostasis is only rudimentary. Previous work from our laboratory has shown that the breakdown of triacylglycerols (TGs) is regulated in a cell-cycle-dependent manner, by activation of the Tgl4 lipase by the major cyclin-dependent kinase Cdc28. The lipases Tgl3 and Tgl4 are required for efficient cell-cycle progression during the G1/S (Gap1/replication phase) transition, at the onset of bud formation, and their absence leads to a cell-cycle delay. We now show that defective lipolysis activates the Swe1 morphogenesis checkpoint kinase that halts cell-cycle progression by phosphorylation of Cdc28 at tyrosine residue 19. Saturated longchain fatty acids and phytosphingosine supplementation rescue the cell-cycle delay in the Tgl3/Tgl4 lipase-deficient strain, suggesting that Swe1 activity responds to imbalanced sphingolipid metabolism, in the absence of TG degradation. We propose a model by which TG-derived sphingolipids are required to activate the protein phosphatase 2A (PP2A Cdc55 ) to attenuate Swe1 phosphorylation and its inhibitory effect on Cdc28 at the G1/S transition of the cell cycle.T he eukaryotic cell cycle is a highly coordinated and conserved process. In addition to DNA replication, one of the major requirements for the cell to progress through the cell cycle is the precise duplication of membrane-enclosed organelles and other cellular components before cell division. Knowledge about the mechanisms regulating (membrane) lipid homeostasis during the cell cycle is scarce (1), however several levels of evidence suggest regulation of key enzymes of lipid metabolism in a cell-cycledependent manner. The PAH1-encoded phosphatidic acid (PA) phosphatase (Pah1), a key enzyme of triacylglycerol (TG) synthesis that provides the TG precursor diacylglycerol (DG), is phosphorylated and inactivated by the cyclin-dependent kinases Cdc28 and Pho85-Pho80 (2, 3). Kurat et al. showed that Tgl4, next to Tgl3, one of the two major TG lipases in yeast and the ortholog of mammalian ATGL (4, 5), is also phosphorylated by Cdc28. In contrast to Pah1, however, Tgl4 is activated by Cdc28 (6). This inverse regulation of Pah1 and Tgl4 by Cdc28-dependent phosphorylation led to the model by which the TG content oscillates during the cell cycle: On the one hand, TG synthesis serves as a buffer for excess de novo generated fatty acids (FAs), and on the other hand, in times of increased demand-that is, at the onset of bud formation and bud growth-Tgl4-catalyzed lipolysis becomes active to provide TG-derived precursors for membrane lipid synthesis (6).TG and membrane phospholipids share the same intermediates, PA and DG; PA is generated by sequential acylation of glycerol-3-phosphate, reactions that mostly take place in the endoplasmic reticulum (ER) membrane (7). The dephosphorylation of PA to DG by the PAH1-encoded PA phosphatase Pah1 is ...

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Section: Lipolysis-defective Mutants Accumulate Saturated and Unsatursupporting

confidence: 80%

Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression

Chauhan

Visram

Cristobal-Sarramian

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Similarly HU sensitivity of the csg2 Δ strain (Liu et al, 2011) was classified as cell-cycle related, and csg2 Δ also showed defective arrest of G1 phase under the stress of linoleic acid and hydroperoxide treatment (Fong et al, 2008). A more recent study (Matmati et al, 2013) showed sur4 Δ, double lag1 Δ, lac1 Δ made cells more sensitive to HU. Moreover, depletion of phytoceramide by overexpressing YPC1 rendered wild type cells sensitive to HU.…”

Section: Phenotypes Of the Yeast Sphingolipid Pathwaymentioning

confidence: 96%

The yeast sphingolipid signaling landscape

Montefusco

Matmati

Hannun

2014

Chemistry and Physics of Lipids

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Sphingolipids are recognized as signaling mediators in a growing number of pathways, and represent potential targets to address many diseases. The study of sphingolipid signaling in yeast has created a number of breakthroughs in the field, and has the potential to lead future advances. The aim of this article is to provide an inclusive view of two major frontiers in yeast sphingolipid signaling. In the first section, several key studies in the field of sphingolipidomics are consolidated to create a yeast sphingolipidome that ranks nearly all known sphingolipid species by their level in a resting yeast cell. The second section presents an overview of most known phenotypes identified for sphingolipid gene mutants, presented with the intention of illuminating not yet discovered connections outside and inside of the field.

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“…In addition, loss of Δψ m decreases TORC1-mediated Sch9p phosphorylation [87]. Despite the fact that the retrograde response is not activated in Δisc1 mutants [28], several cellular responses during the retrograde response are also observed in Δisc1 mutants [18, 20, 44, 92, 94-96, 98]. This indicates that loss of mitochondrial quality, which triggers the retrograde response, interacts with SL homeostasis, and SL signaling activates pathways in Δisc1 mutants that resemble responses to retrograde signaling.…”

Section: Discussionmentioning

confidence: 99%

“…3). For instance, while Rtg2p or Rtg3p upregulate expression of SWE1 [92], encoding the Swe1p protein kinase involved in G2/M transition [93], phytoCer generated by Isc1p regulates Swe1p levels [18, 94]. Additionally, the protein product of RSB1 , whose expression of the encoding gene increases in a Pdr3p-dependent manner upon loss of the mitochondrial genome [44, 95, 96], removes LCBs from the cell [97] and is also increased in Δisc1 mutants [20].…”

Section: The Retrograde Response Interacts With Sphingolipid Homeomentioning

confidence: 99%

Sphingolipids and mitochondrial function in budding yeast

Spincemaille

Matmati

Hannun

et al. 2014

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Sphingolipids (Sls) are not only key components of cellular membranes, but also play an important role as signaling molecules in orchestrating both cell growth and apoptosis. In Saccharomyces cerevisiae, three complex SLs are present and hydrolysis of either of these species is catalyzed by the inositol phosphosphingolipid phospholipase C (Isc1p). Strikingly, mutants deficient in Isc1p display several hallmarks of mitochondrial dysfunction such as the inability to grow on a non-fermentative carbon course, increased oxidative stress and aberrant mitochondrial morphology. Scope of Review In this review, we focus on the pivotal role of Isc1p in regulating mitochondrial function via SL metabolism, and on Sch9p as central signal transducer. Sch9p is one of the main effectors of the target of rapamycin complex 1 (TORC1), which is regarded as a crucial signaling axis for regulation of Isc1p-mediated events. Finally, we describe the retrograde response, a signaling event originating from mitochondria to the nucleus which results in the induction of nuclear target genes. Intriguingly, the retrograde response also interacts with SL homeostasis. Major Conclusions All the above suggests a pivotal signaling role for SLs in maintaining correct mitochondrial function in budding yeast. General Significance Studies with budding yeast provide insight on SL signaling events that affect mitochondrial function.

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Identification of C18:1-Phytoceramide as the Candidate Lipid Mediator for Hydroxyurea Resistance in Yeast

Cited by 32 publications

References 35 publications

Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression

Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression

The yeast sphingolipid signaling landscape

Sphingolipids and mitochondrial function in budding yeast

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