Role of the non‐respiratory pathways in the utilization of molecular oxygen by <i>Saccharomyces cerevisiae</i>

Rosenfeld, Eric; Beauvoit, Bertrand

doi:10.1002/yea.1026

Cited by 133 publications

(118 citation statements)

References 221 publications

(262 reference statements)

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“…Cholesterol biosynthesis consumes 11 molecules of oxygen per sterol (Summons et al, 2006). Yeast do not synthesize ergosterol under anaerobic conditions (Rosenfeld and Beauvoit, 2003), and hypoxia downregulates cholesterol biosynthesis in vertebrate cells (Mukodani et al, 1990;Nguyen et al, 2007). It would be interesting to investigate whether hydroxylated sphingolipids might compensate for cholesterol in cells poorly served by the vascular system, and whether such cells might regulate growth in response to membrane sterol levels.…”

Section: Discussionmentioning

confidence: 99%

Survival strategies of a sterol auxotroph

et al. 2010

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SUMMARYThe high sterol concentration in eukaryotic cell membranes is thought to influence membrane properties such as permeability, fluidity and microdomain formation. Drosophila cannot synthesize sterols, but do require them for development. Does this simply reflect a requirement for sterols in steroid hormone biosynthesis, or is bulk membrane sterol also essential in Drosophila? If the latter is true, how do they survive fluctuations in sterol availability and maintain membrane homeostasis? Here, we show that Drosophila require both bulk membrane sterol and steroid hormones in order to complete adult development. When sterol availability is restricted, Drosophila larvae modulate their growth to maintain membrane sterol levels within tight limits. When dietary sterol drops below a minimal threshold, larvae arrest growth and development in a reversible manner. Strikingly, membrane sterol levels in arrested larvae are dramatically reduced (dropping sixfold on average) in most tissues except the nervous system. Thus, sterols are dispensable for maintaining the basic membrane biophysical properties required for cell viability; these functions can be performed by non-sterol lipids when sterols are unavailable. However, bulk membrane sterol is likely to have essential functions in specific tissues during development. In tissues in which sterol levels drop, the overall level of sphingolipids increases and the proportion of different sphingolipid variants is altered. These changes allow survival, but not growth, when membrane sterol levels are low. This relationship between sterols and sphingolipids could be an ancient and conserved principle of membrane homeostasis.

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Section: Discussionmentioning

confidence: 99%

Survival strategies of a sterol auxotroph

et al. 2010

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“…1 and Ref. 17). Under low oxygen conditions, ergosterol synthesis decreases and Sre1 cleavage is activated.…”

Section: Low Oxygen Increases 4-methylmentioning

confidence: 96%

4-Methyl Sterols Regulate Fission Yeast SREBP-Scap under Low Oxygen and Cell Stress

Hughes¹,

Lee²,

Bien³

et al. 2007

Journal of Biological Chemistry

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In fission yeast, orthologs of mammalian SREBP and Scap, called Sre1 and Scp1, monitor oxygen-dependent sterol synthesis as a measure of cellular oxygen supply. Under low oxygen conditions, sterol synthesis is inhibited, and Sre1 cleavage is activated. However, the sterol signal for Sre1 activation is unknown. In this study, we characterized the sterol signal for Sre1 activation using a combination of Sre1 cleavage assays and gas chromatography sterol analysis. We find that Sre1 activation is regulated by levels of the 4-methyl sterols 24-methylene lanosterol and 4,4-dimethylfecosterol under conditions of low oxygen and cell stress. Both increases and decreases in the level of these ergosterol pathway intermediates induce Sre1 proteolysis in a Scp1-dependent manner. The SREBP ortholog in the pathogenic fungus Cryptococcus neoformans is also activated by high levels of 4-methyl sterols, suggesting that this signal for SREBP activation is conserved among unicellular eukaryotes. Finally, we provide evidence that the sterol-sensing domain of Scp1 is important for regulating Sre1 proteolysis. The conserved mutations Y247C, L264F, and D392N in Scp1 that render Scap insensitive to sterols cause constitutive Sre1 activation. These findings indicate that unlike Scap, fission yeast Scp1 responds to 4-methyl sterols and thus shares properties with mammalian HMG-CoA reductase, a sterol-sensing domain protein whose degradation is regulated by the 4-methyl sterol lanosterol.Lipid homeostasis in mammals is regulated at the transcriptional level by sterol regulatory element-binding proteins (SREBPs), 4 a family of ER membrane-bound transcription factors (1, 2). SREBPs control expression of over 30 genes required for low density lipoprotein uptake and synthesis of fatty acids, triglycerides, phospholipids, and cholesterol (3). SREBP contains two transmembrane segments and is inserted into the ER membrane in a hairpin fashion such that the N and C termini are in the cytosol. The N terminus of SREBP is a basic helixloop-helix leucine zipper (bHLH-zip) transcription factor. The C terminus of SREBP binds SREBP cleavage activating protein (Scap), an ER membrane protein required for the function of SREBP.SREBP transcriptional activity is controlled by cellular cholesterol concentration through a negative feedback system. In cells with high levels of cholesterol, the SREBP-Scap complex is retained in the ER in an inactive state. ER retention is mediated by an interaction of Scap with the ER resident protein Insig (4). A drop in cholesterol levels disrupts the binding of Scap and Insig, facilitating ER exit of SREBP-Scap and transport to the Golgi apparatus. In the Golgi, SREBP is activated by two proteolytic cleavage events mediated by the Site-1 and Site-2 proteases (5). Upon cleavage, the N-terminal bHLH-zip domain of SREBP is released from the membrane and enters the nucleus to activate transcription of target genes required for lipid homeostasis.The sterol-sensing ability of the SREBP pathway is mediated by Scap, a polytopic ER mem...

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“…While Sre1-Scp1 responds to pharmacological inhibition of sterol synthesis, the physiological trigger for Sre1 activation is hypoxia (Hughes et al 2005). Ergosterol synthesis is highly oxygen-consumptive, requiring 12 molecules of dioxygen (Rosenfeld and Beauvoit 2003). Under low oxygen, ergosterol synthesis is inhibited, stimulating Sre1 proteolysis (Fig.…”

Section: Srebp In Fungimentioning

confidence: 99%

Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been

Osborne

Espenshade²

2009

Genes Dev.

234

249

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Sterol regulatory element-binding proteins (SREBPs) are a subfamily of basic helix–loop–helix leucine zipper (bHLH-LZ) transcription factors that are conserved from fungi to humans and are defined by two key features: a signature tyrosine residue in the DNA-binding domain, and a membrane-tethering domain that is a target for regulated proteolysis. Recent studies including genome-wide and model organism approaches indicate SREBPs coordinate cellular lipid metabolism with other cellular physiologic processes. These functions are broadly related as cellular adaptation to environmental changes ranging from nutrient fluctuations to toxin exposure. This review integrates classic features of the SREBP pathway with newer information regarding the regulation and sensing mechanisms that serve to assimilate different cellular physiologic processes for optimal function and growth.

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Role of the non‐respiratory pathways in the utilization of molecular oxygen by Saccharomyces cerevisiae

Cited by 133 publications

References 221 publications

Survival strategies of a sterol auxotroph

Survival strategies of a sterol auxotroph

4-Methyl Sterols Regulate Fission Yeast SREBP-Scap under Low Oxygen and Cell Stress

Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been

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