Control of membrane fluidity: the OLE pathway in focus

Ballweg, Stephanie; Ernst, Robert

doi:10.1515/hsz-2016-0277

Cited by 100 publications

(98 citation statements)

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“…We also studied the unsaturation levels in the principal acyl side‐chains (Fig. B) as a decrease in the degree of unsaturation has been described as a conserved cellular response to reduce membrane fluidity (Ballweg and Ernst, ; Ernst et al ., ). Under our conditions, we observed a significant decrease ( t ‐test, P < 0.05) in the mono‐unsaturated acyl chains (C16:1 and 18:1), as well as a significant increase ( t ‐test, P < 0.05) in saturated fatty acids (C16:0 and 18:0) at different time points in the PC species.…”

Section: Resultsmentioning

confidence: 99%

Membrane fluidification by ethanol stress activates unfolded protein response in yeasts

Navarro-Tapia

Querol

Pérez‐Torrado

2018

Microbial Biotechnology

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SummaryThe toxic effect of ethanol is one of the most important handicaps for many biotechnological applications of yeasts, such as bioethanol production. Elucidation of ethanol stress response will help to improve yeast performance in biotechnological processes. In the yeast Saccharomyces cerevisiae, ethanol stress has been recently described as an activator of the unfolded protein response (UPR), a conserved intracellular signalling pathway that regulates the transcription of ER homoeostasis‐related genes. However, the signal and activation mechanism has not yet been unravelled. Here, we studied UPR's activation after ethanol stress and observed the upregulation of the key target genes, like INO1, involved in lipid metabolism. We found that inositol content influenced UPR activation after ethanol stress and we observed significant changes in lipid composition, which correlate with a major membrane fluidity alteration by this amphipathic molecule. Then, we explored the hypothesis that membrane fluidity changes cause UPR activation upon ethanol stress by studying UPR response against fluidification or rigidification agents and by studying a mutant, erg2, with altered membrane fluidity. The results suggest that the membrane fluidification effects of ethanol and other agents are the signal for UPR activation, a mechanism that has been proposed in higher eukaryotes.

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Section: Resultsmentioning

confidence: 99%

Membrane fluidification by ethanol stress activates unfolded protein response in yeasts

Navarro-Tapia

Querol

Pérez‐Torrado

2018

Microbial Biotechnology

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“…Under this condition, however, the activation of the UPR initiates a detrimental, positive feedback loop. Enforced membrane biogenesis controlled by the UPR causes a more rapid consumption of coenzyme A (CoA)-activated fatty acids in glycerophospholipids, thereby competing with the desaturase Ole1 to oxidize saturated to unsaturated fatty acids (Ballweg & Ernst, 2017). Thus, the activation of the UPR by saturated membrane lipids causes the biosynthesis of even more saturated lipids, inducing more ER-stress and leading to severe morphological changes of the ER and other organelles (Surma et al, 2013;Schneiter & Kohlwein, 1997).…”

Section: Discussionmentioning

confidence: 99%

The molecular recognition of phosphatidic acid by an amphipathic helix in Opi1

Ernst

Gecht

Fischer

et al. 2018

Preprint

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Running title (40 characters):Headgroup selectivity of an amphipathic helix Keywords:Opi1; phosphatidic acid; PA sensor; amphipathic helix; membrane curvature . CC-BY-ND 4.0 International license not peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/250019 doi: bioRxiv preprint first posted online Jan. 18, 2018; Page 2 of 43 Abstract (175 words limit)A key event in cellular physiology is the decision between membrane biogenesis and fat storage. Phosphatidic acid (PA) is an important lipid intermediate and signaling lipid at the branch point of these pathways and constantly monitored by the transcriptional repressor Opi1 to orchestrate lipid metabolism. Here, we report on the mechanism of membrane recognition by Opi1 and identify an amphipathic helix (AH) for the selective binding to membranes containing PA over phosphatidylserine (PS).The insertion of the AH into the hydrophobic core of the membrane renders Opi1 sensitive to the lipid acyl chain composition as an important factor contributing to the regulation of membrane biogenesis. Based on these findings, we rationally designed the membrane binding properties of Opi1 to control its responsiveness in the physiological context. Using extensive molecular dynamics (MD) simulations, we identified two PA-selective three-finger grips that tightly bind the phosphate headgroup, while interacting less intimately and more transiently with PS. This work establishes lipid headgroup selectivity as a new feature in the family of AH-containing membrane property sensors.

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“…Cellular membranes are complex assemblies of proteins and lipids, which collectively determine physical bilayer properties such as membrane viscosity, permeability, and the lateral pressure profile 1–4 . The acyl chain composition of membrane lipids is an important determinant of membrane viscosity and tightly controlled in bacteria 5–7 , fungi 8,9 , worms 10,11 , flies 12 , and vertebrates 13,14 . Saturated lipid acyl chains tend to form non-fluid, tightly packed gel phases, while unsaturated lipid acyl chains fluidize the bilayer.…”

Section: Introductionmentioning

confidence: 99%

“…The prototypical class II sensor Mga2 is crucial for the regulation of membrane viscosity in the baker’s yeast 9,26 (Figure 1A). Its single transmembrane helix (TMH) senses a physicochemical signal in the ER membrane to control a homeostatic response that adjusts membrane lipid saturation via the essential fatty acid cis -Δ 9 -desaturase Ole1 33–35 .…”

Section: Introductionmentioning

confidence: 99%

“…This regulated, ubiquitin/proteasome dependent processing resembles the pathway of ER-associated degradation 38 and was first described for Spt23, a close structural and functional homologue of Mga2 39 . Because Ole1 is the only source for the de novo biosynthesis of unsaturated fatty acids, its tight regulation via Mga2 is essential for maintaining membrane fluidity in this poikilotherm 9,35 .…”

Section: Introductionmentioning

confidence: 99%

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Regulation of lipid saturation without sensing membrane fluidity

Ballweg

Sezgin

Wunnicke

et al. 2019

Preprint

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20Cells maintain membrane fluidity by regulating lipid saturation, but the molecular 21 mechanisms of this homeoviscous adaptation remain poorly understood. Here, we have 22 reconstituted the core machinery for sensing and regulating lipid saturation in baker's yeast 23 to directly characterize its response to defined membrane environments. Using spectroscopic 24 techniques and in vitro ubiquitylation, we uncover a unique sensitivity of the transcriptional 25 regulator Mga2 to the abundance, position, and configuration of double bonds in lipid acyl 26 chains and provide unprecedented insight into the molecular rules of membrane adaptivity. 27 Our data challenge the prevailing hypothesis that membrane viscosity serves as the 28 measured variable for regulating lipid saturation. Rather, we show that the signaling output of 29 Mga2 correlates with the size of a single sensor residue in the transmembrane helix, which 30 senses the lateral pressure and/or compressibility profile in a defined region of the 31 membrane. Our findings suggest that membrane property sensors have evolved remarkable 32 sensitivities to highly specific aspects of membrane structure and dynamics, thus paving the 33 way toward the development of genetically encoded reporters for such membrane properties 34 in the future. 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 Keywords 51 Membrane fluidity, homeoviscous response, lateral pressure profile, physicochemical 52 membrane homeostasis, lipid saturation, membrane property sensors, unsaturated fatty 53 acids, saturated fatty acids, Mga2, Spt23, Ole1, Rsp5, proteasome, ubiquitylation.54 55 Cellular membranes are complex assemblies of proteins and lipids, which collectively 56 determine physical bilayer properties such as membrane viscosity, permeability, and the 57 lateral pressure profile 1-4 . The acyl chain composition of membrane lipids is an important 58 determinant of membrane viscosity and tightly controlled in bacteria 5-7 , fungi 8,9 , worms 10,11 , 59 flies 12 , and vertebrates 13,14 . Saturated lipid acyl chains tend to form non-fluid, tightly packed 60 gel phases, while unsaturated lipid acyl chains fluidize the bilayer. Poikilothermic organisms 61 that cannot control their body temperature must adjust their lipid composition during cold 62 stress to maintain membrane functions-a phenomenon referred to as the homeoviscous 63 adaptation 15-17 . Despite recent advances in identifying candidate sensory, it remains largely 64 unknown how these sensors work on the molecular scale and how they are coordinated for 65 maintaining a physicochemical membrane homeostasis 20,21 . The fact that most, if not all, 66 membrane properties are interdependent is a key challenge for this emerging field. How do 67 cells, for example, balance the need for maintaining membrane viscosity with the need to 68 maintain organelle-specific lateral pressure profiles 22 ? In fact, perturbation of membrane 69 viscosity by genetically targeting fatty acid metabolism leads to complex changes throughout 70 the en...

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Control of membrane fluidity: the OLE pathway in focus

Cited by 100 publications

References 110 publications

Membrane fluidification by ethanol stress activates unfolded protein response in yeasts

Membrane fluidification by ethanol stress activates unfolded protein response in yeasts

The molecular recognition of phosphatidic acid by an amphipathic helix in Opi1

Regulation of lipid saturation without sensing membrane fluidity

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