The Experts below are selected from a list of 55497 Experts worldwide ranked by ideXlab platform
Johanna A. Bouwstra - One of the best experts on this subject based on the ideXlab platform.
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Selectivity in cornified envelop binding of Ceramides in human skin and the role of LXR inactivation on ceramide binding.
Biochimica et Biophysica Acta, 2019Co-Authors: Walter Boiten, Richard W. J. Helder, Jeroen Van Smeden, Johanna A. BouwstraAbstract:Abstract The cornified lipid envelope (CLE) is a lipid monolayer covalently bound to the outside of corneocytes and is part of the stratum corneum (SC). The CLE is suggested to act as a scaffold for the unbound SC lipids. By profiling the bound CLE Ceramides, a new subclass was discovered and identified as an omega-hydroxylated dihydrosphingosine (OdS) ceramide. Bound glucosylCeramides were observed in superficial SC layers of healthy human skin. To investigate the relation between bound and unbound SC Ceramides, the composition of both fractions was analyzed and compared. Selectivity in ceramide binding towards unsaturated Ceramides and Ceramides with a shorter chain length was observed. The selectivity in ceramide species bound to the cornified envelope is thought to have a physiological function in corneocyte flexibility. Next, it was examined if skin models exhibit an altered bound ceramide composition and if the composition was dependent on liver X-receptor (LXR) activation. The effects of an LXR agonist and antagonist on the bound Ceramides composition of a full thickness model (FTM) were analyzed. In FTMs, a decreased amount of bound Ceramides was observed compared to native human skin. Furthermore, FTMs had a bound ceramide fraction which consisted mostly of unsaturated and shorter Ceramides. The LXR antagonist had a normalizing effect on the FTM bound ceramide composition. The agonist exhibited minimal effects. We show that ceramide binding is a selective process, yet, still is contingent on lipid synthesized.
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topically applied Ceramides interact with the stratum corneum lipid matrix in compromised ex vivo skin
Pharmaceutical Research, 2018Co-Authors: Tineke Berkers, Gert S. Gooris, Dani Visscher, Johanna A. BouwstraAbstract:To determine whether formulations containing Ceramides (including a ceramide with a long hydroxyl acyl chain linked to a linoleate, CER EOS) and fatty acids are able to repair the skin barrier by normalizing the lipid organization in stratum corneum (SC). The formulations were applied on a skin barrier repair model consisting of ex vivo human skin from which SC was removed by stripping. The effect of formulations on the lipid organization and conformational ordering in the regenerated SC were analyzed using Fourier transform infrared spectroscopy and small angle X-ray diffraction. Application of the formulation containing only one ceramide on regenerating SC resulted in a higher fraction of lipids adopting an orthorhombic organization. A similar fraction of lipids forming an orthorhombic organization was observed after application of a formulation containing two Ceramides and a fatty acid on regenerating SC. No effects on the lamellar lipid organization were observed. Application of a formulation containing either a single ceramide or two Ceramides and a fatty acid on regenerating SC, resulted in a denser lateral lipid packing of the SC lipids in compromised skin. The strongest effect was observed after application of a formulation containing a single ceramide.
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Topically Applied Ceramides Interact with the Stratum Corneum Lipid Matrix in Compromised Ex Vivo Skin
Pharmaceutical Research, 2018Co-Authors: Tineke Berkers, Gert S. Gooris, Dani Visscher, Johanna A. BouwstraAbstract:Purpose To determine whether formulations containing Ceramides (including a ceramide with a long hydroxyl acyl chain linked to a linoleate, CER EOS) and fatty acids are able to repair the skin barrier by normalizing the lipid organization in stratum corneum (SC). Methods The formulations were applied on a skin barrier repair model consisting of ex vivo human skin from which SC was removed by stripping. The effect of formulations on the lipid organization and conformational ordering in the regenerated SC were analyzed using Fourier transform infrared spectroscopy and small angle X-ray diffraction . Results Application of the formulation containing only one ceramide on regenerating SC resulted in a higher fraction of lipids adopting an orthorhombic organization. A similar fraction of lipids forming an orthorhombic organization was observed after application of a formulation containing two Ceramides and a fatty acid on regenerating SC. No effects on the lamellar lipid organization were observed. Conclusions Application of a formulation containing either a single ceramide or two Ceramides and a fatty acid on regenerating SC, resulted in a denser lateral lipid packing of the SC lipids in compromised skin. The strongest effect was observed after application of a formulation containing a single ceramide.
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applying a vernix caseosa based formulation accelerates skin barrier repair by modulating lipid biosynthesis
Journal of Lipid Research, 2017Co-Authors: Walter Boiten, Tineke Berkers, Samira Absalah, Jeroen Van Smeden, A P M Lavrijsen, Johanna A. BouwstraAbstract:: Restoring the lipid homeostasis of the stratum corneum (SC) is a common strategy to enhance skin barrier function. Here, we used a ceramide containing vernix caseosa (VC)-based formulation and were able to accelerate barrier recovery in healthy volunteers. The recovery was examined over 16 days by monitoring trans-epidermal water loss (TEWL) after barrier disruption by tape-stripping. Four skin sites were used to examine the effects of both treatment and barrier recovery. After 16 days, samples were harvested at these sites to examine the SC ceramide composition and lipid organization. Changes in ceramide profiles were identified using principal component analysis. After barrier recovery, the untreated sites showed increased levels of ceramide subclass AS and Ceramides with a 34 total carbon-atom chain length, while the mean ceramide chain length was reduced. These changes were diminished by treatment with the studied formulation, which concurrently increased the formulated Ceramides. Correlations were observed between SC lipid composition, lipid organization, and TEWL, and changes in the ceramide subclass composition suggest changes in the ceramide biosynthesis. These results suggest that VC-based formulations enhance skin barrier recovery and are attractive candidates to treat skin disorders with impaired barrier properties.
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quantitative analysis of Ceramides using a novel lipidomics approach with three dimensional response modelling
Biochimica et Biophysica Acta, 2016Co-Authors: Walter Boiten, Samira Absalah, Johanna A. Bouwstra, Rob J Vreeken, Jeroen Van SmedenAbstract:In the outermost layer of the skin, the stratum corneum (SC), Ceramides form a diverse and essential pool of lipids. Due to their diversity and the limited availability of synthetic standards it is challenging to quantitatively analyse all SC Ceramides independently. We aim to perform a detailed analysis of Ceramides on SC harvested from in vivo and ex vivo skin, therefore, a LC/MS method was developed in which all steps from sample acquisition until data analysis were examined and optimized. Improving extraction efficiency of Ceramides resulted in an increase in efficiency from 71.5% to 99.3%. It was shown that sample harvesting by tape-stripping in vivo was accurate and precise. A full scan MS method was developed, compatible with all sample types, enabling simultaneously qualitative and quantitative data analysis. A novel three dimensional response model was constructed to quantify all detected Ceramides from full scan data using a limited amount of synthetic Ceramides. The application is demonstrated on various SC sample types. When ex vivo SC was regenerated during human skin culture, increases are observed in the amount of the ceramide sphingosine subclasses, in mono unsaturated Ceramides (which have an cis-double bond in the acyl chain), and Ceramides with a short C34 carbon chain (Ceramides with a total carbon chain of 34 carbon atoms), compared with native human skin. These changes in ceramide levels are also often encountered in diseased skin.
Antonio Gómez-muñoz - One of the best experts on this subject based on the ideXlab platform.
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Control of inflammatory responses by ceramide, sphingosine 1-phosphate and ceramide 1-phosphate.
Progress in Lipid Research, 2015Co-Authors: Antonio Gómez-muñoz, Natalia Presa, Ana Gomez-larrauri, Io-guané Rivera, Miguel Trueba, Marta OrdoñezAbstract:Inflammation is a network of complex processes involving a variety of metabolic and signaling pathways aiming at healing and repairing damage tissue, or fighting infection. However, inflammation can be detrimental when it becomes out of control. Inflammatory mediators involve cytokines, bioactive lipids and lipid-derived metabolites. In particular, the simple sphingolipids Ceramides, sphingosine 1-phosphate, and ceramide 1-phosphate have been widely implicated in inflammation. However, although ceramide 1-phosphate was first described as pro-inflammatory, recent studies show that it has anti-inflammatory properties when produced in specific cell types or tissues. The biological functions of Ceramides and sphingosine 1-phosphate have been extensively studied. These sphingolipids have opposing effects with Ceramides being potent inducers of cell cycle arrest and apoptosis, and sphingosine 1-phosphate promoting cell growth and survival. However, the biological actions of ceramide 1-phosphate have only been partially described. Ceramide 1-phosphate is mitogenic and anti-apoptotic, and more recently, it has been demonstrated to be key regulator of cell migration. Both sphingosine 1-phosphate and ceramide 1-phosphate are also implicated in tumor growth and dissemination. The present review highlights new aspects on the control of inflammation and cell migration by simple sphingolipids, with special emphasis to the role played by ceramide 1-phosphate in controlling these actions.
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Interaction of Ceramides, Sphingosine, and Sphingosine 1-Phosphate in Regulating DNA Synthesis and Phospholipase D Activity
Journal of Biological Chemistry, 1995Co-Authors: Antonio Gómez-muñoz, David W. Waggoner, Lori O'brien, David N. BrindleyAbstract:Abstract C2- and C6-Ceramides (N-acetylsphingosine and N-hexanoylsphingosine, respectively) abolished the stimulation of DNA synthesis by sphingosine 1-phosphate in rat fibroblasts. This inhibition by ceramide was partially prevented by insulin. C2-ceramide did not alter the stimulation of DNA synthesis by insulin and decreased the sphingosine-induced stimulation by only 16%. The Ceramides did not significantly modify the actions of sphingosine or sphingosine 1-phosphate in decreasing cAMP concentrations. C2- and C6-Ceramides blocked the activation of phospholipase D by sphingosine 1-phosphate, and this inhibition was not affected by insulin. Okadaic acid decreased the activation of phospholipase D by sphingosine 1-phosphate and did not reverse the inhibitory effect of C2-ceramide on this activation. Therefore, this effect of C2-ceramide is unlikely to involve the stimulation of phosphoprotein phosphatase activity. Sphingosine did not activate phospholipase D activity significantly after 10 min. C2-ceramide stimulated the conversion of exogenous [3H]sphingosine 1-phosphate to sphingosine and ceramide in fibroblasts. Ceramides can inhibit some effects of sphingosine 1-phosphate by stimulating its degradation via a phosphohydrolase that also hydrolyzes phosphatidate. Furthermore, C2- and C6-Ceramides stimulated ceramide production from endogenous lipids, and this could propagate the intracellular signal. This work demonstrates that controlling the production of ceramide versus sphingosine and sphingosine 1-phosphate after sphingomyelinase activation could have profound effects on signal transduction.
Tineke Berkers - One of the best experts on this subject based on the ideXlab platform.
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Topically Applied Ceramides Interact with the Stratum Corneum Lipid Matrix in Compromised Ex Vivo Skin
Pharmaceutical Research, 2018Co-Authors: Tineke Berkers, Gert S. Gooris, Dani Visscher, Johanna A. BouwstraAbstract:Purpose To determine whether formulations containing Ceramides (including a ceramide with a long hydroxyl acyl chain linked to a linoleate, CER EOS) and fatty acids are able to repair the skin barrier by normalizing the lipid organization in stratum corneum (SC). Methods The formulations were applied on a skin barrier repair model consisting of ex vivo human skin from which SC was removed by stripping. The effect of formulations on the lipid organization and conformational ordering in the regenerated SC were analyzed using Fourier transform infrared spectroscopy and small angle X-ray diffraction . Results Application of the formulation containing only one ceramide on regenerating SC resulted in a higher fraction of lipids adopting an orthorhombic organization. A similar fraction of lipids forming an orthorhombic organization was observed after application of a formulation containing two Ceramides and a fatty acid on regenerating SC. No effects on the lamellar lipid organization were observed. Conclusions Application of a formulation containing either a single ceramide or two Ceramides and a fatty acid on regenerating SC, resulted in a denser lateral lipid packing of the SC lipids in compromised skin. The strongest effect was observed after application of a formulation containing a single ceramide.
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topically applied Ceramides interact with the stratum corneum lipid matrix in compromised ex vivo skin
Pharmaceutical Research, 2018Co-Authors: Tineke Berkers, Gert S. Gooris, Dani Visscher, Johanna A. BouwstraAbstract:To determine whether formulations containing Ceramides (including a ceramide with a long hydroxyl acyl chain linked to a linoleate, CER EOS) and fatty acids are able to repair the skin barrier by normalizing the lipid organization in stratum corneum (SC). The formulations were applied on a skin barrier repair model consisting of ex vivo human skin from which SC was removed by stripping. The effect of formulations on the lipid organization and conformational ordering in the regenerated SC were analyzed using Fourier transform infrared spectroscopy and small angle X-ray diffraction. Application of the formulation containing only one ceramide on regenerating SC resulted in a higher fraction of lipids adopting an orthorhombic organization. A similar fraction of lipids forming an orthorhombic organization was observed after application of a formulation containing two Ceramides and a fatty acid on regenerating SC. No effects on the lamellar lipid organization were observed. Application of a formulation containing either a single ceramide or two Ceramides and a fatty acid on regenerating SC, resulted in a denser lateral lipid packing of the SC lipids in compromised skin. The strongest effect was observed after application of a formulation containing a single ceramide.
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applying a vernix caseosa based formulation accelerates skin barrier repair by modulating lipid biosynthesis
Journal of Lipid Research, 2017Co-Authors: Walter Boiten, Tineke Berkers, Samira Absalah, Jeroen Van Smeden, A P M Lavrijsen, Johanna A. BouwstraAbstract:: Restoring the lipid homeostasis of the stratum corneum (SC) is a common strategy to enhance skin barrier function. Here, we used a ceramide containing vernix caseosa (VC)-based formulation and were able to accelerate barrier recovery in healthy volunteers. The recovery was examined over 16 days by monitoring trans-epidermal water loss (TEWL) after barrier disruption by tape-stripping. Four skin sites were used to examine the effects of both treatment and barrier recovery. After 16 days, samples were harvested at these sites to examine the SC ceramide composition and lipid organization. Changes in ceramide profiles were identified using principal component analysis. After barrier recovery, the untreated sites showed increased levels of ceramide subclass AS and Ceramides with a 34 total carbon-atom chain length, while the mean ceramide chain length was reduced. These changes were diminished by treatment with the studied formulation, which concurrently increased the formulated Ceramides. Correlations were observed between SC lipid composition, lipid organization, and TEWL, and changes in the ceramide subclass composition suggest changes in the ceramide biosynthesis. These results suggest that VC-based formulations enhance skin barrier recovery and are attractive candidates to treat skin disorders with impaired barrier properties.
Marco Colombini - One of the best experts on this subject based on the ideXlab platform.
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Ceramide channels: destabilization by Bcl-xL and role in apoptosis ☆
Biochimica et Biophysica Acta, 2015Co-Authors: Kai-ti Chang, Andriy Anishkin, Gauri A Patwardhan, Leah J Siskind, Levi J. Beverly, Marco ColombiniAbstract:Abstract Ceramide is a bioactive sphingolipid involved in mitochondrial-mediated apoptosis. Our data suggest that Ceramides directly regulate a key initiation step in apoptosis: mitochondrial outer membrane permeabilization (MOMP). MOMP allows release of intermembrane space proteins to the cytosol, inducing the execution of the cell. Ceramides form channels in planar phospholipid membranes and outer membranes of isolated mitochondria, channels large enough to facilitate passage of proteins released during MOMP. Bcl-xL inhibits MOMP in vivo and inhibits the formation of ceramide channels in vitro . However the significance of Bcl-xL's regulation of ceramide channel formation within cells was untested. We engineered Bcl-xL point mutations that specifically affect the interaction between ceramide and Bcl-xL to probe the mechanism of ceramide channel regulation and the role of ceramide channels in apoptosis. Using these mutants and fluorescently-labeled ceramide, we identified the hydrophobic groove on Bcl-xL as the critical ceramide binding site and regulator of ceramide channel formation. Bcl-xL mutants with weakened interaction with ceramide also have reduced ability to interfere with ceramide channel formation. Some mutants have similar altered ability to inhibit both ceramide and Bax channel formation, whereas others act differentially, suggesting distinct but overlapping binding sites. To probe the relative importance of these channels in apoptosis, Bcl-xL mutant proteins were stably expressed in Bcl-xL deficient cells. Weakening the inhibition of either Bax or ceramide channels decreased the ability of Bcl-xL to protect cells from apoptosis in a stimulus-dependent manner. These studies provide the first in vivo evidence for the role of ceramide channels in MOMP.
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Ceramide channels: destabilization by Bcl-xL and role in apoptosis.
Biochimica et biophysica acta, 2015Co-Authors: Kai-ti Chang, Andriy Anishkin, Gauri A Patwardhan, Leah J Siskind, Levi J. Beverly, Marco ColombiniAbstract:Ceramide is a bioactive sphingolipid involved in mitochondrial-mediated apoptosis. Our data suggest that Ceramides directly regulate a key initiation step in apoptosis: mitochondrial outer membrane permeabilization (MOMP). MOMP allows release of intermembrane space proteins to the cytosol, inducing the execution of the cell. Ceramides form channels in planar phospholipid membranes and outer membranes of isolated mitochondria, channels large enough to facilitate passage of proteins released during MOMP. Bcl-xL inhibits MOMP in vivo and inhibits the formation of ceramide channels in vitro. However the significance of Bcl-xL's regulation of ceramide channel formation within cells was untested. We engineered Bcl-xL point mutations that specifically affect the interaction between ceramide and Bcl-xL to probe the mechanism of ceramide channel regulation and the role of ceramide channels in apoptosis. Using these mutants and fluorescently-labeled ceramide, we identified the hydrophobic groove on Bcl-xL as the critical ceramide binding site and regulator of ceramide channel formation. Bcl-xL mutants with weakened interaction with ceramide also have reduced ability to interfere with ceramide channel formation. Some mutants have similar altered ability to inhibit both ceramide and Bax channel formation, whereas others act differentially, suggesting distinct but overlapping binding sites. To probe the relative importance of these channels in apoptosis, Bcl-xL mutant proteins were stably expressed in Bcl-xL deficient cells. Weakening the inhibition of either Bax or ceramide channels decreased the ability of Bcl-xL to protect cells from apoptosis in a stimulus-dependent manner. These studies provide the first in vivo evidence for the role of ceramide channels in MOMP.
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Bax and Bcl-xL exert their regulation on different sites of the ceramide channel.
Biochemical Journal, 2012Co-Authors: Meenu N. Perera, Zdzislaw M. Szulc, Yuri K. Peterson, Robert Bittman, Marco ColombiniAbstract:The present study demonstrates the important structural features of ceramide required for proper regulation, binding and identification by both pro-apoptotic and anti-apoptotic Bcl-2 family proteins. The C-4=C-5 trans-double bond has little influence on the ability of Bax and Bcl-xL to identify and bind to these channels. The stereochemistry of the headgroup and access to the amide group of ceramide is indispensible for Bax binding, indicating that Bax may interact with the polar portion of the ceramide channel facing the bulk phase. In contrast, Bcl-xL binding to ceramide channels is tolerant of stereochemical changes in the headgroup. The present study also revealed that Bcl-xL has an optimal interaction with long-chain Ceramides that are elevated early in apoptosis, whereas short-chain Ceramides are not well regulated. Inhibitors specific for the hydrophobic groove of Bcl-xL, including 2-methoxyantimycin A3, ABT-737 and ABT-263 provide insights into the region of Bcl-xL involved in binding to ceramide channels. Molecular docking simulations of the lowest-energy binding poses of Ceramides and Bcl-xL inhibitors to Bcl-xL were consistent with the results of our functional studies and propose potential binding modes.
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Sphingosine, a Product of Ceramide Hydrolysis, Influences the Formation of Ceramide Channels
Biophysical Journal, 2006Co-Authors: Matthew J. Elrick, Sharon Fluss, Marco ColombiniAbstract:Ceramides are known to have a regulatory function in apoptosis, including the release of cytochrome c and other proapoptotic factors from the mitochondrial intermembrane space. Ceramides can form large, stable channels in the outer mitochondrial membrane, leading to the proposal that ceramide channels are the pathway through which these proteins are released. Here, we report that sphingosine, a product of ceramide hydrolysis by ceramidase, is capable of destabilizing ceramide channels, leading to their disassembly. Sphingosine is directly responsible for the disassembly of ceramide channels in planar membrane experiments and markedly reduces the ability of ceramide to induce the release of intermembrane space proteins from mitochondria in vitro. Low concentrations of both L and D sphingosine potentiate the release of intermembrane space proteins by long-chain ceramide and channel formation in liposomes. These results provide evidence for a mechanism by which the disassembly of ceramide channels, as initiated by ceramidase, could be accelerated by the direct interaction of the hydrolysis product with the ceramide channels themselves. This mechanism therefore could form a positive feedback loop for rapid shut-down of ceramide channels. However, potentiation of ceramide channel formation is also possible and thus both effects could influence the propensity for mitochondria-mediated apoptosis.
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ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins
Journal of Biological Chemistry, 2002Co-Authors: Leah J Siskind, Richard Kolesnick, Marco ColombiniAbstract:Abstract Ceramides are known to play a major regulatory role in apoptosis by inducing cytochrome c release from mitochondria. We have previously reported that C2- and C16-ceramide, but not dihydroceramide, form large channels in planar membranes (Siskind, L. J., and Colombini, M. (2001)J. Biol. Chem. 275, 38640–38644). Here we show that Ceramides do not trigger a cytochrome c secretion or release mechanism, but simply raise the permeability of the mitochondrial outer membrane, via ceramide channel formation, to include small proteins. Exogenously added reduced cytochromec was able to freely permeate the mitochondrial outer membrane with entry to and exit from the intermembrane space facilitated by Ceramides in a dose- and time-dependent manner. The permeability pathways were eliminated upon removal of C2-ceramide by bovine serum albumin, thus ruling out a detergent-like effect of C2-ceramide on membranes. Ceramide channels were not specific to cytochrome c, as Ceramides induced release of adenylate kinase, but not fumerase from isolated mitochondria, showing some specificity of these channels for the outer mitochondrial membrane. SDS-PAGE results show that Ceramides allow release of intermembrane space proteins with a molecular weight cut-off of about 60,000. These results indicate that the ceramide-induced membrane permeability increases in isolated mitochondria are via ceramide channel formation and not a release mechanism, as the channels that allow cytochrome c to freely permeate are reversible, and are not specific to cytochromec.
Joost C M Holthuis - One of the best experts on this subject based on the ideXlab platform.
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A switchable ceramide transfer protein for dissecting the mechanism of ceramide-induced mitochondrial apoptosis.
FEBS letters, 2020Co-Authors: Amrita Jain, Shashank Dadsena, Joost C M HolthuisAbstract:Mitochondrial translocation of Ceramides triggers Bax-dependent apoptosis. To elucidate how Ceramides activate Bax and commit cells to death, we developed a switchable version of the ceramide transfer protein CERT, sCERT. Upon its drug-induced recruitment to mitochondria, sCERT retains the ability to bind VAP proteins in the ER and catalyzes mitochondrial import of externally added fluorescent Ceramides. Mitochondrial recruitment of sCERT also triggers mitochondrial translocation of Bax. The ability of mitochondria-bound sCERT to mediate ceramide import and Bax translocation requires both its START domain and ongoing ceramide biosynthesis. These data extend our previous finding that mistargeting of ER Ceramides to mitochondria specifically activates Bax and establish sCERT as a novel tool to dissect the underlying mechanism in a time-resolved manner.
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sphingomyelin synthase related protein smsr is a suppressor of ceramide induced mitochondrial apoptosis
Journal of Cell Science, 2014Co-Authors: Fikadu G Tafesse, Ana M Vacaru, Elleke Fenna Bosma, Martin Hermansson, Amrita Jain, Angelika Hilderink, Pentti Somerharju, Joost C M HolthuisAbstract:ABSTRACT Cells synthesize Ceramides in the endoplasmic reticulum (ER) as precursors for sphingolipids to form an impermeable plasma membrane. As Ceramides are engaged in apoptotic pathways, cells would need to monitor their levels closely to avoid killing themselves during sphingolipid biosynthesis. How this is accomplished remains to be established. Here we identify SMSr (SAMD8), an ER-resident ceramide phosphoethanolamine (CPE) synthase, as a suppressor of ceramide-mediated cell death. Disruption of SMSr catalytic activity causes a rise in ER Ceramides and their mislocalization to mitochondria, triggering a mitochondrial pathway of apoptosis. Blocking de novo ceramide synthesis, stimulating ceramide export from the ER or targeting a bacterial ceramidase to mitochondria rescues SMSr-deficient cells from apoptosis. We also show that SMSr-catalyzed CPE production, although essential, is not sufficient to suppress ceramide-induced cell death and that SMSr-mediated ceramide homeostasis requires the N -terminal sterile α-motif, or SAM domain, of the enzyme. These results define ER Ceramides as bona fide transducers of mitochondrial apoptosis and indicate a primary role of SMSr in monitoring ER ceramide levels to prevent inappropriate cell death during sphingolipid biosynthesis.
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sphingomyelin synthase related protein smsr controls ceramide homeostasis in the er
Journal of Cell Biology, 2009Co-Authors: Ana M Vacaru, Fikadu G Tafesse, Martin Hermansson, Pentti Somerharju, Philipp Ternes, Vangelis Kondylis, Jos F Brouwers, Catherine Rabouille, Joost C M HolthuisAbstract:Ceramides are central intermediates of sphingolipid metabolism with critical functions in cell organization and survival. They are synthesized on the cytosolic surface of the endoplasmic reticulum (ER) and transported by ceramide transfer protein to the Golgi for conversion to sphingomyelin (SM) by SM synthase SMS1. In this study, we report the identification of an SMS1-related (SMSr) enzyme, which catalyses the synthesis of the SM analogue ceramide phosphoethanolamine (CPE) in the ER lumen. Strikingly, SMSr produces only trace amounts of CPE, i.e., 300-fold less than SMS1-derived SM. Nevertheless, blocking its catalytic activity causes a substantial rise in ER ceramide levels and a structural collapse of the early secretory pathway. We find that the latter phenotype is not caused by depletion of CPE but rather a consequence of ceramide accumulation in the ER. Our results establish SMSr as a key regulator of ceramide homeostasis that seems to operate as a sensor rather than a converter of Ceramides in the ER.
