A Eukaryotic Sensor for Membrane Lipid Saturation

Covino, Roberto; Ballweg, Stephanie; Stordeur, Claudius; Michaelis, Jonas B.; Puth, Kristina; Wernig, Florian; Bahrami, Amir Houshang; Ernst, Andreas; Hummer, Gerhard; Ernst, Robert

doi:10.1016/j.bpj.2016.11.2750

Cited by 35 publications

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“…2) Mutagenesis of individual TMH residues (V543-F551) including three aromatic residues lining one side of the TMH – one of which being the best-crosslinking residue F544C - causes no relevant functional defects (Figure S3A). These findings are notable because aromatic residues have been implicated in lipid/membrane sensing in other systems (37, 45, 46). 3) Our crosslinking data provide no evidence for a rotational re-organization of the TMHs during lipid bilayer stress (Figure 3C,D, Figure S3C).…”

Section: Discussionmentioning

confidence: 89%

“…scored the oligomerization propensity of IRE1α in cells via bimolecular fluorescence complementation in palmitate-treated cells and suggested that the increased lipid saturation might induce a conformational switch in the TMH region, which relies on a tryptophan (W457) as putative sensing residue and a conserved leucine zipper motif (SxxLxxx) involving serine 450 (37, 44). Intriguingly, such a rotation-based mechanism of sensing would be reminiscent of the lipid saturation sensor Mga2 from baker’s yeast controlling the expression of the essential fatty acid desaturase-encoding gene OLE1 (45, 46).…”

Section: Discussionmentioning

confidence: 99%

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Cysteine crosslinking in native membranes establishes the transmembrane architecture of Ire1

Vaeth

Mattes

Reinhard

et al. 2019

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36The endoplasmic reticulum (ER) is a key organelle of membrane biogenesis and 37 crucial for the folding of both membrane and secretory proteins. Stress sensors of the 38 unfolded protein response (UPR) monitor the unfolded protein load in the ER and 39 convey effector functions for the maintenance of ER homeostasis. More recently, it 40 became clear that aberrant compositions of the ER membrane, referred to as lipid 41 bilayer stress, are equally potent activators of the UPR with important implications in 42 obesity and diabetes. How the distinct signals from lipid bilayer stress and proteotoxic 43 stress are processed by the highly conserved UPR transducer Ire1 remains unknown. 44Here, we have generated a functional, cysteine-less variant of Ire1 and performed 45 systematic cysteine crosslinking experiments to establish the transmembrane 46 architecture of signaling-active clusters in native membranes. We show that the 47 transmembrane helices of two neighboring Ire1 molecules adopt an X-shaped 48 configuration and that this configuration is independent of the primary cause for ER 49 stress. Based on these findings, we propose that different forms of stress converge in 50 a single, signaling-active conformation of Ire1.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Cysteine crosslinking in native membranes establishes the transmembrane architecture of Ire1

Vaeth

Mattes

Reinhard

et al. 2019

Preprint

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“…Environmental or chemical stresses affect lipid metabolism, which plays a role in maintaining membrane homeostasis and cell growth, a case in point is the membrane unsaturated fatty acids to saturated fatty acids ratio being increased under high-pressure homogenization stress, which enables the strain to avoid damage (36). Transcription factors, such as Mga2 and Upc2 that enable changes in the expression of lipid biosynthesis genes may change lipid composition indirectly (18, 38).…”

Section: Discussionmentioning

confidence: 99%

Engineering of membrane complex sphingolipids improves osmotic tolerance of Saccharomyces cerevisiae

Zhu

Yin

Luo

et al. 2019

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20In order to enhance the growth performance of S. cerevisiae under harsh environmental conditions, 21 mutant XCG001, which tolerates up to 1.5M NaCl, was isolated via adaptive laboratory evolution 22 IMPORTANCE 33This study demonstrated a novel strategy for manipulation membrane complex sphingolipids to 34 enhance S. cerevisiae tolerance to osmotic stress. Osmotic tolerance was related to sphingolipid 35 acyl chain elongase, Elo2, via transcriptome analysis of the wild-type strain and an osmotic tolerant 36 strain generated from ALE. Overexpression of ELO2 increased complex sphingolipid with longer 37 3 acyl chain, thus improved membrane integrity and osmotic tolerance. 38 KERWORDS: Adaptive laboratory evolution; osmotic tolerance; membrane engineering; 39 complex sphingolipid; membrane integrity 40

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“…Eukaryotic cells use sensor proteins possessing refined mechanisms to monitor physicochemical properties of their organellar membranes and to adjust lipid metabolism during stress, metabolic adaptation, and development 10,24,26–31 . These sensor proteins can be categorized into three classes, based on topological considerations 20,21 : Class I sensors interrogate surface properties of cellular membranes, such as the surface charge and molecular packing density as reported for amphipathic lipid packing sensor (ALPS) motif containing proteins and other amphipathic helix containing proteins 32 .…”

Section: Introductionmentioning

confidence: 99%

Regulation of lipid saturation without sensing membrane fluidity

Ballweg

Sezgin

Wunnicke

et al. 2019

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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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A Eukaryotic Sensor for Membrane Lipid Saturation

Cited by 35 publications

References 0 publications

Cysteine crosslinking in native membranes establishes the transmembrane architecture of Ire1

Cysteine crosslinking in native membranes establishes the transmembrane architecture of Ire1

Engineering of membrane complex sphingolipids improves osmotic tolerance of Saccharomyces cerevisiae

Regulation of lipid saturation without sensing membrane fluidity

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