Regulation of Gene Expression through a Transcriptional Repressor that Senses Acyl-Chain Length in Membrane Phospholipids

Hofbauer, Harald F.; Schopf, Florian H.; Schleifer, Hannes; Knittelfelder, Oskar; Pieber, Bartholomäus; Rechberger, Gerald; Wolinski, Heimo; Gaspar, María L.; Kappe, C. Oliver; Stadlmann, Johannes; Mechtler, Karl; Zenz, Alexandra; Lohner, Karl; Tehlivets, Oksana; Henry, Susan A.

doi:10.1016/j.devcel.2014.04.025

Cited by 80 publications

(125 citation statements)

References 68 publications

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“…Moreover, a study reported that the knockout of SNF1 results in transcriptional pattern that differed from one on lipid accumulation devaluing the important role of this gene in lipid accumulation [69]. One alternative solution is to use hyperactive mutant Acc1 for higher malonyl-CoA production and consequently higher TAG accumulation, comprised of longer chain fatty acids, without need for snf1 inactivation [72]. This can contribute to a carbon flux re-direction from citric acid to lipid production.…”

Section: Discussionmentioning

confidence: 99%

Engineering Yarrowia lipolytica for Enhanced Production of Lipid and Citric Acid

Abghari

Chen

2017

Fermentation

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Increasing demand for plant oil for food, feed, and fuel production has led to food-fuel competition, higher plant lipid cost, and more need for agricultural land. On the other hand, the growing global production of biodiesel has increased the production of glycerol as a by-product. Efficient utilization of this by-product can reduce biodiesel production costs. We engineered Yarrowia lipolytica (Y. lipolytica) at various metabolic levels of lipid biosynthesis, degradation, and regulation for enhanced lipid and citric acid production. We used a one-step double gene knock-in and site-specific gene knock-out strategy. The resulting final strain combines the overexpression of homologous DGA1 and DGA2 in a POX-deleted background, and deletion of the SNF1 lipid regulator. This increased lipid and citric acid production in the strain under nitrogen-limiting conditions (C/N molar ratio of 60). The engineered strain constitutively accumulated lipid at a titer of more than 4.8 g/L with a lipid content of 53% of dry cell weight (DCW). The secreted citric acid reached a yield of 0.75 g/g (up to~45 g/L) from pure glycerol in 3 days of batch fermentation using a 1-L bioreactor. This yeast cell factory was capable of simultaneous lipid accumulation and citric acid secretion. It can be used in fed-batch or continuous bioprocessing for citric acid recovery from the supernatant, along with lipid extraction from the harvested biomass.

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Section: Discussionmentioning

confidence: 99%

Engineering Yarrowia lipolytica for Enhanced Production of Lipid and Citric Acid

Abghari

Chen

2017

Fermentation

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“…The kinase responsible for the human acetyl-CoA carboxylase phosphorylation is the AMP-activated protein kinase (AMPK) which in yeast is named Snf1p [8,9]. Snf1p/AMPK might not be the only kinase that regulates acetyl-CoA carboxylase activity, as in yeast, 30% of the Acc1p pool is phosphorylated in a snf1Δ background [10]. Protein phosphatase responsible for Acc1p dephosphorylation and subsequent activation remains unknown, although studies in mammalian and yeast models suggest that a PP2A-like protein phosphatase may be involved [11].…”

Section: Introductionmentioning

confidence: 99%

A Chemogenomic Screen Reveals Novel Snf1p/AMPK Independent Regulators of Acetyl-CoA Carboxylase

Bozaquel-Morais¹,

Madeira²,

Venâncio³

et al. 2017

PLoS ONE

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Acetyl-CoA carboxylase (Acc1p) is a key enzyme in fatty acid biosynthesis and is essential for cell viability. To discover new regulators of its activity, we screened a Saccharomyces cerevisiae deletion library for increased sensitivity to soraphen A, a potent Acc1p inhibitor. The hits identified in the screen (118 hits) were filtered using a chemical-phenotype map to exclude those associated with pleiotropic drug resistance. This enabled the identification of 82 ORFs that are genetic interactors of Acc1p. The main functional clusters represented by these hits were “transcriptional regulation”, “protein post-translational modifications” and “lipid metabolism”. Further investigation of the “transcriptional regulation” cluster revealed that soraphen A sensitivity is poorly correlated with ACC1 transcript levels. We also studied the three top unknown ORFs that affected soraphen A sensitivity: SOR1 (YDL129W), SOR2 (YIL092W) and SOR3 (YJR039W). Since the C18/C16 ratio of lipid acyl lengths reflects Acc1p activity levels, we evaluated this ratio in the three mutants. Deletion of SOR2 and SOR3 led to reduced acyl lengths, suggesting that Acc1p is indeed down-regulated in these strains. Also, these mutants showed no differences in Snf1p/AMPK activation status and deletion of SNF1 in these backgrounds did not revert soraphen A sensitivity completely. Furthermore, plasmid maintenance was reduced in sor2Δ strain and this trait was shared with 18 other soraphen A sensitive hits. In summary, our screen uncovered novel Acc1p Snf1p/AMPK-independent regulators.

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“…In addition to its metabolic role as a key intermediate in DAG, TAG, and phospholipid synthesis, PA also has signaling function, which operates through its specific interaction with the transcriptional repressor Opi1. This binding of Opi1 to PA regulates the subcellular distribution of the repressor and hence its nuclear repressing activity (Loewen et al 2004;Henry et al 2012;Hofbauer et al 2014).…”

Section: Glycerophospholipidsmentioning

confidence: 99%

Analyzing and Understanding Lipids of Yeast: A Challenging Endeavor

Kohlwein

2017

Cold Spring Harb Protoc

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Lipids are essential biomolecules with diverse biological functions, ranging from building blocks for all biological membranes to energy substrates, signaling molecules, and protein modifiers. Despite advances in lipid analytics by mass spectrometry, the extraction and quantitative analysis of the diverse classes of lipids are still an experimental challenge. Yeast is a model organism that provides several advantages for studying lipid metabolism, because most biosynthetic pathways are well described and a great deal of information is available on the regulatory mechanisms that control lipid homeostasis. In addition, the composition of yeast lipids is much less complex than that of mammalian lipids, making yeast an excellent reference system for studying lipid-associated cell functions.

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Regulation of Gene Expression through a Transcriptional Repressor that Senses Acyl-Chain Length in Membrane Phospholipids

Cited by 80 publications

References 68 publications

Engineering Yarrowia lipolytica for Enhanced Production of Lipid and Citric Acid

Engineering Yarrowia lipolytica for Enhanced Production of Lipid and Citric Acid

A Chemogenomic Screen Reveals Novel Snf1p/AMPK Independent Regulators of Acetyl-CoA Carboxylase

Analyzing and Understanding Lipids of Yeast: A Challenging Endeavor

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