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evolution
Lass proteins are known to contain a TLC [TRAM/Lag1p/ CLN8 (ceroid-lipofuscinoses, neuronal 8)] homology domain with the Lag1 motif. Lass family members Lass2, Lass4 and Lass5, but not Lass1, also contain a HOX (homeobox) domain
evolution
murine Lass6 is a member of the mouse Lass family. It exhibits the highest identity with Lass5 (61.7% identity and 68.2% similarity) and the lowest identity with Lass1 (16.0% identity and 27.4%similarity). Lass proteins are known to contain a TLC [TRAM/Lag1p/ CLN8 (ceroid-lipofuscinoses, neuronal 8)] homology domain with the Lag1 motif. Lass family members Lass2, Lass4 and Lass5, but not Lass1, also contain a HOX (homeobox) domain
evolution
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schlank belongs to the ceramide family, schlank falls into the Lass family, phylogenetic tree of Lass family members and TRAM proteins, overview
malfunction
the TcCERS1 gene is able to functionally complement the lethality of a lag1DELTA lac1DELTA double deletion yeast mutant in which the acyl-CoA-dependent CerS is not detectable
malfunction
decreased enzyme expression induces endoplasmic reticulum stress and apoptosis in head and neck squamous carcinoma cells but not in A-549, MCF-7, or SW-480 cells, which are derived from lung, breast, and colon cancer, respectively, detailed overview
malfunction
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ceramide synthase-specific inhibitor fumonisin B1 suppresses hypoxia-reoxygenation-induced ceramide generation and provides protection against hypoxia-reoxygenation-induced EndoG release, DNA fragmentation, and cell death
malfunction
CerS6 knockdown might decrease apoptosis compared to normal irradiated HeLa cells
malfunction
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disruption of the de novo pathway of sphingolipid biosynthesis may be a critical in the diseases that have been associated with consumption of fumonisins. Fusarium moniliforme causes equine leucoencephalomalacia, porcine pulmonary edem syndrome, and liver cancer in rats
malfunction
inhibition of CerS is able to protect from cell death. Moreover, this protection occurs downstream or independently of mitochondrial permeabilization. Inhibition of CerS greatly inhibits plasma membrane permeabilization. Combined knockdown of CerS5 and CerS6 is able to decrease long-chain ceramide accumulation and plasma membrane permeabilization. Individual CerS knockdown does not significantly inhibit total ceramide accumulation, CerS6 knockdown clearly decreases C14:0- and C16:0-Cer basally and reduces their accumulation following UV-C irradiation, CerS5 knockdown has no appreciable effects on Cer levels. Inhibition of CerS but not de novo synthesis inhibits plasma membrane rupture that is not specific to UV-C irradiation or MCF-7 cells
malfunction
inhibition of CerS is able to protect from cell death. Moreover, this protection occurs downstream or independently of mitochondrial permeabilization. Inhibition of CerS greatly inhibits plasma membrane permeabilization. Combined knockdown of CerS5 and CerS6 is able to decrease long-chain ceramide accumulation and plasma membrane permeabilization. Individual CerS knockdown does not significantly inhibit total ceramide accumulation, knockdown of CerS6 actually even increases total ceramide levels. CerS5 knockdown has no appreciable effects on Cer levels. Inhibition of CerS but not de novo synthesis inhibits plasma membrane rupture that is not specific to UV-C irradiation or MCF-7 cells
malfunction
knockdown using fumonisin B 1 or LASS5 small, interfering RNA reduced ceramide synthase activity by 78% or 45%, respectively. Exogenously expressed LASS5 in lung epithelia is membrane-associated, triggering increased ceramide synthesis. Compared with control cells, cells transfected with LASS5 siRNA exhibit a 43% increase in rates of phosphatidylcholine synthesis
malfunction
overexpression of CerS5 increases apoptosis in HeLa cells. CerS2 and CerS5 overexpression significantly alters apoptosis
malfunction
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P-element insertions into the DLag1 locus cause defects in larval growth and fat metabolism. Schlank mutants also show reduction of storage fat, which is deposited as triacylglyerols in the fat body. Hemizygous schlank mutants show a delay of larval development and pronounced growth defects, which depend on the strength of the alleles (Figure 1A-C). Mutants carrying the stronger schlankG0349 allele fail to grow in the larval stages, although they feed. After about 3days, these animals die as small larvae, which morphologically correspond in size to first instar larvae. In contrast, hemizygous animals carrying the weaker schlankG0061 allele are developmentally delayed. Phenotypes, overview. Modulation of schlank activity correlates with the rate of ceramide de novo synthesis
malfunction
profiles of non-hydroxylated and 2-hydroxy-ceramides in transgenic HeLa cells expressing different CerS isozymes and or different specific interfence RNAs, overview
malfunction
RNAi against CerS6 results in a specific decrease in intracellular C16-ceramide and protects SW-480 cells against TRAIL-mediated apoptosis while increasing CerS6 expression sensitizes SW-620 cells to TRAIL. Downregulation of CerS6 does not interfere with caspase activation but appears to inhibit translocation of activated caspase-3 into the nucleus
malfunction
upon incubation of HEK cells with inhibitor FTY720, an increase in ceramide levels is observed, with no change in endogenous sphinganine levels. Similar increases are observed for hexosylceramide and sphingomyelin. Moreover, levels of C18-C22-ceramide are significantly increased, as were levels of C18-C22-hexosylceramide and C18-C22-sphingomyelin. This result is consistent with a complex mode of interaction of FTY720 with CerS, perhaps involving an allosteric element that is not preserved in vitro, whereby ceramide synthesis is stimulated in cells despite its inhibition by FTY720 in vitro
malfunction
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disruption of the de novo pathway of sphingolipid biosynthesis may be a critical in the diseases that have been associated with consumption of fumonisins. Fusarium moniliforme causes equine leucoencephalomalacia, porcine pulmonary edem syndrome, and liver cancer in rats
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malfunction
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knockdown using fumonisin B 1 or LASS5 small, interfering RNA reduced ceramide synthase activity by 78% or 45%, respectively. Exogenously expressed LASS5 in lung epithelia is membrane-associated, triggering increased ceramide synthesis. Compared with control cells, cells transfected with LASS5 siRNA exhibit a 43% increase in rates of phosphatidylcholine synthesis
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metabolism
due to the highly dynamic nature of sphingolipid metabolism, alterations in the expression of CerS6 may have impacts beyond increased generation of C16-ceramide
metabolism
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ceramide synthases use long-chain bases, sphinganine or sphingosine, and FA-CoAs with varying chain length to produce (dihydro)ceramide, which is a precursor metabolite for all sphingolipids
metabolism
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ceramide, a key intermediate in sphingolipid metabolism, is synthesized by acylation of sphinganine followed by dehydrogenation of dihydroceramide to ceramide
metabolism
LASS5 expression alone reduces choline incorporation into phosphatidylcholine by 26%, whereas coexpression of LASS5 with sphingomyelinase produces a nearly 40% reduction in phosphatidylcholine synthesis
metabolism
regulation of CerS isozymes, overview. The interplay among the CerS proteins takes place in a stress stimulus-, cell type- and subcellular compartment-specific manner. CerS2 and CerS5 overexpression significantly alters apoptosis, determination of ionizing radiation-induced mitochondrial ceramide elevations via CerS2, 5, and 6, overview. CerS2 and CerS5 overexpressions defines opposing roles in radiation-induced mitochondrial apoptosis
metabolism
regulation of CerS isozymes, overview. The interplay among the CerS proteins takes place in a stress stimulus-, cell type- and subcellular compartment-specific manner. CerS6 overexpression yields no significant differences in IR-induced apoptosis compared to empty vector-transfected cells. Determination of ionizing radiation-induced mitochondrial ceramide elevations via CerS2, 5, and 6, overview
metabolism
regulation of sphingolipid metabolism by UV-C irradiation, overview. Ceramide species that are the least abundant (e.g. C18-Cer, C18:1-Cer, C20-Cer, C22:1-Cer, etc.) exhibit the greatest fold increases. More abundant ceramide species (e.g. C16-Cer, C24-Cer, and C24:1-Cer) show more modest fold changes, although they account for much more of the overall increase in ceramides
metabolism
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serine palmitoyltransferase, 3-dehydrosphinganine reductase, and sphinganine N-acyltransferase are responsible for the first steps in sphingolipid biosynthesis forming 3-oxosphinganine, sphinganine, and dihydroceramide, respectively
metabolism
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the conversion of sphinganine to N-acyl-sphinganines is thought to precede via introduction of the 4,5-trans double bond of sphingosine
metabolism
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the enzyme catalyzes a step in the ceramide biosynthesis, the CoA-dependent addition of a long-chain fatty acid to sphinganine. Sphinganine might be converted to sphingosine first. Pathway regulation, overview
metabolism
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the enzyme catalyzes a step in the ceramide biosynthesis, the CoA-dependent addition of a long-chain fatty acid to sphinganine. Sphinganine might be converted to sphingosine first. Pathway regulation, overview
metabolism
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the sphingomyelin pathway, which is initiated by sphingomyelin hydrolysis to generate the second messenger ceramide, signals apoptosis for tumor necrosis factor a, Fas, and ionizing radiation
metabolism
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the sphingomyelin pathway, which is initiated by sphingomyelin hydrolysis to generate the second messenger ceramide, signals apoptosis for tumor necrosis factor a, Fas, and ionizing radiation
metabolism
the production of ceramide isoforms is regulated by the stoichiometry of the three ceramide synthase isoform Cer1, Cer2, Cer3 of Cryptococcus neoformans in the presence of different substrate chain lengths. When Cer1 and Cer2 are coexpressed, C24 phytoceramide is the major product. When Cer1 and Cer3 are co-expressed, the enzyme activity shifts to C18 and C26 fatty acyl CoA products
metabolism
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the conversion of sphinganine to N-acyl-sphinganines is thought to precede via introduction of the 4,5-trans double bond of sphingosine
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metabolism
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LASS5 expression alone reduces choline incorporation into phosphatidylcholine by 26%, whereas coexpression of LASS5 with sphingomyelinase produces a nearly 40% reduction in phosphatidylcholine synthesis
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metabolism
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ceramide, a key intermediate in sphingolipid metabolism, is synthesized by acylation of sphinganine followed by dehydrogenation of dihydroceramide to ceramide
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physiological function
activity of CerS in the salvage pathway in which sphingosine is recycled into ceramides. Upregulation of CerS6 expression increases C16-ceramide generation at the expense of very long chain ceramides. Increased expression of acid ceramidase in response to CerS6 expression occurs via a JNK-AP1-dependent mechanism and is important for survival. Enzyme CerS6 may transcriptionally activate the expression of acid ceramidase (ASAH1)
physiological function
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ceramide plays a role in the cell signaling pathway involved in apoptosis. Ceramide synthase is essential for endonuclease-mediated death of renal tubular epithelial cells induced by hypoxia reoxygenation. Mainly, enhanced ceramide generation is the result of hydrolysis of sphingomyelin by sphingomyelinases. Role of ceramide synthase in enhanced ceramide generation, overview. Exposure of cells to hypoxia-reoxygenation results in a significant increase in ceramide synthase activity without any significant change in acid or neutral sphingomyelinase. Ceramide synthase-dependent ceramide generation is a key modulator of EndoG-mediated cytotoxicity in hypoxia-reoxygenation injury to renal tubular epithelial cells
physiological function
ceramide synthase 6 modulates TRAIL sensitivity and nuclear translocation of active caspase-3 in colon cancer cells. Ceramide synthase 6 (CerS6 also known as longevity assurance homolog 6/LASS6) preferentially generates C16-ceramide and can influence TRAIL susceptibility. CerS6 may regulate events at the nuclear membrane and allow late stage apoptotic signaling
physiological function
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ceramide synthase mediates daunorubicin-induced apoptosis, an alternative mechanism for generating death signals. Ceramide synthesis appears obligatory for daunorubicin-induced apoptosis, since fumonisin B1, a natural specific inhibitor of ceramide synthase, blocks daunorubicin-induced ceramide elevation and apoptosis. Ceramide mimics daunorubicin in inducing apoptosis
physiological function
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ceramide synthase mediates daunorubicin-induced apoptosis, an alternative mechanism for generating death signals. Ceramide synthesis appears obligatory for daunorubicin-induced apoptosis, since fumonisin B1, a natural specific inhibitor of ceramide synthase, blocks daunorubicin-induced ceramide elevation and apoptosis. Ceramide mimics daunorubicin in inducing apoptosis
physiological function
ceramides are synthesized by ceramide synthases through the addition of a variable length fatty acid to the amine group of a sphingoid base. In mammalian cells, the sphingoid base used for de novo ceramide synthesis is usually the C18:0 lipid dihydrosphingosine. Ceramide synthesis is catalyzed by a family of six ceramide synthases (CERS1-6), each of which preferentially transfers fatty acids of different lengths to the amine group of dihydrosphingosine
physiological function
CerS4 plays a critical role in beta-cells apoptosis induced by glucolipotoxicity through the synthesis of specific ceramide species such as C18:0. Glucolipotoxicity activates caspase 3/7 through ceramide accumulation in INS-1 cells. Transient overexpression of HA-tagged CerS4 increases the levels of ceramides C18:0 and C22:0 by 20%, but has no effect on the accumulation of ceramides C16:0 and C24:0. CerS4 potentiates palmitate-induced beta-cell apoptosis. Overexpression of HA-tagged CerS4 potentiates ceramide accumulation induced by stearate, which is particularly toxic for beta-cells
physiological function
differences in the expression patterns of CerS family members may play an important role in the production of the CER/2-hydroxy ceramide (CER) compositions of different chain lengths observed in different cell types and even in the altered production that occurring during keratinocyte differentiation
physiological function
distinct roles and modes of regulation for each of the ceramide synthases in Arabidopsis thaliana sphingolipid metabolism. Ceramides are organizing components of sphingolipids in the eukaryotic cell. Three ceramide synthase isoforms are found in Arabidopsis thaliana each with specific substrate preferences and sensitivity to inhibitors and activators, overview. Isozyme LOH2 is required for the synthesis of ceramides with dihydroxy-long-chain bases and C16 fatty acids
physiological function
isozyme CerS5 sensitizes cells to doxorubicin and vincristine
physiological function
LASS5 is the major ceramide synthase gene product involved in sphingolipid production that may also regulate PtdCho metabolism in pulmonary epithelia. LASS5 regulates surfactant phosphatidylcholine (PtdCho) synthesis
physiological function
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schlank is involved in the de novo synthesis of a broad range of ceramides, the key metabolites of sphingolipid biosynthesis. Schlank can positively regulate fatty acid synthesis by promoting the expression of sterol-responsive element-binding protein (SREBP) and SREBP-target genes. It further prevents lipolysis by downregulating the expression of triacylglycerol lipase. Schlank negatively regulates the expression of lipases in the fat body, downregulating lipolysis. Schlank is a regulator of the balance between lipogenesis and lipolysis in Drosophila melanogaster. Schlank can act as a positive regulator of SREBP-dependent lipogenesis in Drosophila larvae. Role for ceramide synthases in regulating body fat metabolism. Schlank has both a maternal and a zygotic supply and explains the residual mRNA and protein activity in schlankG0349-mutant animals
physiological function
selective tissue and subcellular distribution of the six mammalian CerS isoforms, combined with distinct fatty acyl chain length substrate preferences, implicate differential functions of specific ceramide species in cellular signaling. Ionizing radiation (IR) induces de novo synthesis of ceramide to influence HeLa cell apoptosis by specifically activating isozymes CerS isoforms 2, 5, and 6 that generate opposing anti- and pro-apoptotic ceramides in mitochondrial membranes. Isozymes CerS5 and CerS6 each confer about 50% of the C16:0 CerS baseline synthetic activity, both are required for IR-induced activity. IR-induced CerS-mediated ceramide generation, and subsequent apoptosis, occurs in a cell-type specific manner. CerS2 and CerS5 overexpressions defines opposing roles in radiation-induced mitochondrial apoptosis
physiological function
selective tissue and subcellular distribution of the six mammalian CerS isoforms, combined with distinct fatty acyl chain length substrate preferences, implicate differential functions of specific ceramide species in cellular signaling. Ionizing radiation (IR) induces de novo synthesis of ceramide to influence HeLa cell apoptosis by specifically activating isozymes CerS isoforms 2, 5, and 6 that generate opposing anti- and pro-apoptotic ceramides in mitochondrial membranes. Isozymes CerS5 and CerS6 each confer about 50% of the C16:0 CerS baseline synthetic activity, both are required for IR-induced activity. IR-induced CerS-mediated ceramide generation, and subsequent apoptosis, occurs in a cell-type specific manner. CerS6 overexpression yields no significant differences in IR-induced apoptosis compared to empty vector-transfected cells
physiological function
sphingolipid ceramides are widely implicated in the regulation of programmed cell death or apoptosis. CerS5 and CerS6 regulate C16:0-Cer synthesis. Ceramide synthase inhhibitor fumonisin B1 inhibits cell death, suggesting the presence of a ceramide synthase (CerS)-dependent, sphingosine-derived pool of ceramide in regulating programmed cell death. This pool does not regulate the mitochondrial pathway, but it partially regulates activation of caspase-7 and is necessary for late plasma membrane permeabilization. Mechanisms of its generation and regulatory role during apoptosis, overview
physiological function
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a Lag1 deletion mutant does not have a reduction in total sphingolipid levels. Additional deletion of C4 hydroxylase Sur2 causes a reduction in levels of all phytosphingolipids
physiological function
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a Lag1 deletion mutant does not have a reduction in total sphingolipid levels. Additional deletion of C4 hydroxylase Sur2 causes a reduction in levels of all phytosphingolipids, and de novo synthesis of sphingolipids is disrupted in Lac1/Sur2 deletion strains. Loss of Lac1 but not Lag1 affects strain resistance to increased temperature
physiological function
CerS6 overexpression elevates TNFalpha secretion via p38 mitogen-activated protein kinase activation. The treatment of CerS6 overexpressing cells with palmitate synergistically increases cytokine secretion. Neither palmitate treatment nor CerS6 overexpression alter lipopolysaccharide-induced cytokine secretion
physiological function
inhibition by fumosinin and siRNA for isoforms CerS5 or CerS6 suppresses myristate-induced C14-ceramide generation and XBP1 splicing. Increased XBP1 splicing induces the downstream expression of IL-6 in a CerS5/CerS6-dependent manner. A myristate-enriched milk fat-based diet, but not a lard-based diet, increases C14-ceramide, XBP1 splicing and IL-6 expression in vivo
physiological function
inhibition by fumosinin and siRNA for isoforms CerS5 or CerS6 suppresses myristate-induced C14-ceramide generation and XBP1 splicing. Increased XBP1 splicing induces the downstream expression of IL-6 in a CerS5/CerS6-dependent manner. A myristate-enriched milk fat-based diet, but not a lard-based diet, increases C14-ceramide,XBP1 splicing and IL-6 expression in vivo
physiological function
nonspecific CerS reduction with fumonisin B1 reduces PLIN2 protein
physiological function
the average survival of mice infected with wild-type Cryptococcus neoformans is about 25 days, infection with a Cer2 deletion strain causes aout 70% mortality. The lipid profile of the deletion strain is perturbed from wild-type. The deletion strain shows little to no depletion of lipids but a marked increase in dihydrosphingosine, C18 dihydroceramide, and total short-chain GlcCeramides as well as abundance of most C18 lipids in the inositolphosphoryl ceramide pathway
physiological function
the average survival of mice infected with wild-type Cryptococcus neoformans is about 25 days, infection with a Cer3 deletion strain causes aout 70% mortality. The lipid profile of the deletion strain is perturbed from wild-type. The deletion strain shows significant depletion of C26 phytoceramides in acidic conditions and a decrease in lipids along the GlcCer branch of the pathway as well as a decrease in C24 and C26 lipids in the inositol phosphorylceramide pathway under alkaline conditions
physiological function
the average survival of mice infected with wild-type Cryptococcus neoformans is about 25 days, while all mice infected with a Cer1 deletion strain survive. The deletion strain cells are not observed to progress to the brain of infected mice. The lipid profile of the deletion strain is significantly perturbed from wild-type. Cer1 is the major ceramide synthase responsible for using C18 fatty acyl CoA to generate C18 ceramides. Deletion strain cells have cell division defects leading to the development of elongated cells with a smaller capsule, they show gross morphological defects and inability to complete cytokinesis
physiological function
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LASS5 is the major ceramide synthase gene product involved in sphingolipid production that may also regulate PtdCho metabolism in pulmonary epithelia. LASS5 regulates surfactant phosphatidylcholine (PtdCho) synthesis
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additional information
chimeric mutant CerS5:TM:CerS2-HA displays slightly more activity using C16-CoA as substrate than CerS5, but remarkably, CerS2 activity measured using C22-CoA is elevated by 3fold. Isozymes CerS5 and CerS6 modulate CerS2 activity upon co-expression. This increase in CerS2 activity is abolished using a noncatalytically active form of CerS5 in the constitutive dimer (CerS5HH:TM:CerS2-HA), demonstrating that optimal CerS2 activity depends on an interaction with a catalytically active form of CerS5
additional information
recombinant FLAG-tagged CerS6 localizes primarily to the perinuclear region
additional information
the N-terminus is essential for catalytic activity
additional information
the N-terminus is essential for catalytic activity
additional information
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the N-terminus is essential for catalytic activity