Tricalbin-Mediated Contact Sites Control ER Curvature to Maintain Plasma Membrane Integrity

Collado, Javier; Kalemanov, Maria; Martínez-Sánchez, Antonio; Campelo, Felix; Baumeister, Wolfgang; Stefan, Christopher J.; Fernández-Busnadiego, Rubén

doi:10.2139/ssrn.3371409

Cited by 2 publications

(1 citation statement)

References 110 publications

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“…The SPOTS complex (SPT, Orm1/2, Tsc3, and Sac1) is present in both, the nuclear as well as the cortical ER of yeast cells [7,31]. The cortical ER has recently been shown to be closely associated with the plasma membrane in ER-membrane contact sites [40,41]. Thus, Gnp1-mediated serine uptake could be directly coupled to SP biosynthesis.…”

Section: Plos Geneticsmentioning

confidence: 99%

Uptake of exogenous serine is important to maintain sphingolipid homeostasis in Saccharomyces cerevisiae

et al. 2020

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Sphingolipids are abundant and essential molecules in eukaryotes that have crucial functions as signaling molecules and as membrane components. Sphingolipid biosynthesis starts in the endoplasmic reticulum with the condensation of serine and palmitoyl-CoA. Sphingolipid biosynthesis is highly regulated to maintain sphingolipid homeostasis. Even though, serine is an essential component of the sphingolipid biosynthesis pathway, its role in maintaining sphingolipid homeostasis has not been precisely studied. Here we show that serine uptake is an important factor for the regulation of sphingolipid biosynthesis in Saccharomyces cerevisiae. Using genetic experiments, we find the broad-specificity amino acid permease Gnp1 to be important for serine uptake. We confirm these results with serine uptake assays in gnp1Δ cells. We further show that uptake of exogenous serine by Gnp1 is important to maintain cellular serine levels and observe a specific connection between serine uptake and the first step of sphingolipid biosynthesis. Using mass spectrometry-based flux analysis, we further observed imported serine as the main source for de novo sphingolipid biosynthesis. Our results demonstrate that yeast cells preferentially use the uptake of exogenous serine to regulate sphingolipid biosynthesis. Our study can also be a starting point to analyze the role of serine uptake in mammalian sphingolipid metabolism.

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Section: Plos Geneticsmentioning

confidence: 99%

Uptake of exogenous serine is important to maintain sphingolipid homeostasis in Saccharomyces cerevisiae

et al. 2020

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Uptake of exogenous serine is important to maintain sphingolipid homeostasis inSaccharomyces cerevisiae

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Bogdanowski

et al. 2020

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43Sphingolipids are abundant and essential molecules in eukaryotes that have crucial 44 functions as signaling molecules and as membrane components. Sphingolipid biosynthesis 45 starts in the endoplasmic reticulum with the condensation of serine and palmitoyl-CoA. 46Sphingolipid biosynthesis is highly regulated to maintain sphingolipid homeostasis. Even 47 though, serine is an essential component of the sphingolipid biosynthesis pathway, its role in 48 maintaining sphingolipid homeostasis has not been precisely studied. Here we show that 49 serine uptake is an important factor for the regulation of sphingolipid biosynthesis in 50 Saccharomyces cerevisiae. Using genetic experiments, we find the broad-specificity amino 51 acid permease Gnp1 to be important for serine uptake. We confirm these results with serine 52 uptake assays in gnp1 cells. We further show that uptake of exogenous serine by Gnp1 is 53 important to maintain cellular serine levels and observe a specific connection between serine 54 uptake and the first step of sphingolipid biosynthesis. Using mass spectrometry-based flux 55 analysis, we further observed imported serine as the main source for de novo sphingolipid 56 biosynthesis. Our results demonstrate that yeast cells preferentially use the uptake of 57 exogenous serine to regulate sphingolipid biosynthesis. Our study can also be a starting point 58 to analyze the role of serine uptake in mammalian sphingolipid metabolism. 59 60 61 62 63 64 65 66 67 Author Summary 68 Sphingolipids (SPs) are membrane lipids globally required for eukaryotic life. In contrast to 69other lipid classes, SPs cannot be stored in the cell and therefore their levels have to be tightly 70 regulated. Failure to maintain sphingolipid homeostasis can result in pathologies including 71 neurodegeneration, childhood asthma and cancer. However, we are only starting to 72 understand how SP biosynthesis is adjusted according to need. In this study, we use genetic 73 and biochemical methods to show that the uptake of exogenous serine is necessary to 74 maintain SP homeostasis in Saccharomyces cerevisiae. Serine is one of the precursors of long 75 chain bases in cells, the first intermediate of SP metabolism. Our results suggest that the 76 uptake of serine is directly coupled to SP biosynthesis at ER-plasma membrane contact sites. 77Overall, our study identifies serine uptake as a novel regulatory factor of SP homeostasis. 78While we use yeast as a discovery tool, these results also provide valuable insights into 79 mammalian SP biology especially under pathological conditions. 80 81 82 83 84 85 86 87 88 89 90 91 [1]. In contrast to glycerol-phospholipids (GPLs) and sterols, SPs cannot be stored in the cell. 96

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Tricalbin-Mediated Contact Sites Control ER Curvature to Maintain Plasma Membrane Integrity

Cited by 2 publications

References 110 publications

Uptake of exogenous serine is important to maintain sphingolipid homeostasis in Saccharomyces cerevisiae

Uptake of exogenous serine is important to maintain sphingolipid homeostasis in Saccharomyces cerevisiae

Uptake of exogenous serine is important to maintain sphingolipid homeostasis inSaccharomyces cerevisiae

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