Expression of the ORMDLS, Modulators of Serine Palmitoyltransferase, Is Regulated by Sphingolipids in Mammalian Cells

Gupta, Sita D.; Gable, Kenneth; Alexaki, Aikaterini; Chandris, Panagiotis; Proia, Richard L.; Dunn, Teresa M.; Harmon, Jeffrey M.

doi:10.1074/jbc.m114.588236

Cited by 44 publications

(50 citation statements)

References 29 publications

(42 reference statements)

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“…This result confi rms that while at endogenous levels of SPT, ORMDL levels are suffi cient to control SPT activity; elevation of SPT upsets that ratio, which is corrected by overexpression of ORMDL3 . Similar results have recently been reported in HEK293 cells ( 19 ). Changes in levels of sphingosine do not follow the pattern of the other sphingolipids, being reduced by SPT overexpression.…”

Section: Resultssupporting

confidence: 89%

“…3C ). This may refl ect a difference in endogenous levels of ORMDLs in the HeLa cells used in the experiments reported here and the HEK293 cells utilized by Gupta et al ( 19 ). Alternatively the timing and levels of SPT expression may be important for the effect of SPT expression on ORMDL levels.…”

Section: Low-level Ormdl3 Overexpression In Airway Epithelial Cells Rmentioning

confidence: 89%

“…Only when all three isoforms are depleted by siRNA transfection in HeLa cells is ORMDLdependent regulation of sphingolipid biosynthesis lost ( 3 ). Harmon and colleagues report that all three ORMDL isoforms equivalently inhibit overexpressed SPT ( 19 ). The independent function of the three isoforms is therefore unresolved.…”

Section: Low-level Ormdl3 Overexpression In Airway Epithelial Cells Rmentioning

confidence: 99%

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ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis

Siow

Sunkara

Dunn

et al. 2015

Journal of Lipid Research

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The ORM1 ( Saccharomyces cerevisiae )-like proteins (ORMDLs) and their yeast orthologs, the ORMs, regulate the initiating and rate-limiting enzyme in sphingolipid biosynthesis, serine palmitoyltransferase (SPT) ( 1-4 ). The three ORMDL isoforms (ORMDL1-3) are small (17.5 kDa) hydrophobic membrane proteins that are situated in the endoplasmic reticulum along with SPT. The three isoforms are highly homologous and their functions appear to be redundant at the cellular level ( 3, 4 ). The ORMDLs are negative regulators of SPT and mediate the homeostatic regulation of SPT in response to cellular sphingolipid levels. siRNA depletion of the ORMDLs results in elevated sphingolipid synthesis under control conditions and reverses the homeostatic inhibition of sphingolipid synthesis resulting from elevated cellular sphingolipid content ( 1,3,4 ). The Orms and ORMDLs form stable physical complexes with SPT ( 1 ), even under conditions in which the ORMDLs are minimally inhibiting SPT. In yeast, the Orm regulatory activity is controlled by Orm phosphorylation. This may not be the case for the mammalian ORMDLs, which lack the sequences that are phosphorylated in the yeast Orms. Clinical interest in ORMDL function has been sparked by the observation that SNPs adjacent to the ORMDL3 gene are highly correlated with Abstract The ORM1 ( Saccharomyces cerevisiae )-like proteins (ORMDLs) and their yeast orthologs, the Orms, are negative homeostatic regulators of the initiating enzyme in sphingolipid biosynthesis, serine palmitoyltransferase (SPT). Genome-wide association studies have established a strong correlation between elevated expression of the endoplasmic reticulum protein ORMDL3 and risk for childhood asthma. Here we test the notion that elevated levels of ORMDL3 decrease sphingolipid biosynthesis. This was tested in cultured human bronchial epithelial cells (HBECs) (an immortalized, but untransformed, airway epithelial cell line) and in HeLa cells (a cervical adenocarcinoma cell line). Surprisingly, elevated ORMDL3 expression did not suppress de novo biosynthesis of sphingolipids. We determined that ORMDL is expressed in functional excess relative to SPT at normal levels of expression. ORMDLs and SPT form stable complexes that are not increased by elevated ORMDL3 expression. Although sphingolipid biosynthesis was not decreased by elevated ORMDL3 expression, the steady state mass levels of all major sphingolipids were marginally decreased by low level ORMDL3 over-expression in HBECs. These data indicate that the contribution of ORMDL3 to asthma risk may involve changes in sphingolipid metabolism, but that the connection is complex. 3 February 2015. Published, JLR Papers in Press, February 17, 2015 DOI 10.1194 Abbreviations: C6 , ceramide-N -hexanoyl-D-erythro-sphingosine; HBEC, human bronchial epithelial cell; IP, immunoprecipitation; ORMDL, ORM1 ( Saccharomyces cerevisiae )-like protein; scSPT, single-chain serine palmitoyltransferase; SPT, serine palmitoyltransferase; SPTLC1, serine palmitoyltransferase long chain base ...

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Section: Resultssupporting

confidence: 89%

Section: Low-level Ormdl3 Overexpression In Airway Epithelial Cells Rmentioning

confidence: 89%

Section: Low-level Ormdl3 Overexpression In Airway Epithelial Cells Rmentioning

confidence: 99%

See 1 more Smart Citation

ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis

Siow

Sunkara

Dunn

et al. 2015

Journal of Lipid Research

Self Cite

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“…These findings suggested that yeast ORM proteins are negative regulators of sphingolipid biosynthesis and act through the inhibition of SPT. This conclusion was later confirmed in other studies using cells of various origin, including rice (66), mice (67), and human cell lines (68)(69)(70)(71).…”

Section: -Ketodihydrosphinganine Reductasesupporting

confidence: 67%

“…The fact that expression of hLCB1 did not change after increased SPT activity indicates that autoregulation of SPT expression is not a major mechanism for the regulation of sphingolipid biosynthesis. It was also shown that the main signal to induce ORMDL expression comes from ceramides rather than long-chain bases (69).…”

Section: The Role Of Ormdls In Immune Response Regulationmentioning

confidence: 99%

The role of ORMDL proteins, guardians of cellular sphingolipids, in asthma

Paulenda

Dráber

2016

Allergy

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To cite this article: Paulenda T, Draber P. The role of ORMDL proteins, guardians of cellular sphingolipids, in asthma. AbstractA family of widely expressed ORM-like (ORMDL) proteins has been recently linked to asthma in genomewide association studies in humans and extensively explored in in vivo studies in mice. ORMDL proteins are key regulators of serine palmitoyltransferase, an enzyme catalyzing the initial step of sphingolipid biosynthesis. Sphingolipids play prominent roles in cell signaling and response to stress, and they affect the mechanistic properties of cellular membranes. Deregulation of sphingolipid biosynthesis and their recycling has been proven to support and even cause several diseases including allergy, inflammation, and asthma. ORMDL3, the most extensively studied member of the ORMDL family, has been shown to be important for endoplasmic reticulum homeostasis by regulating the unfolded protein response and calcium response. In immune cells, ORMDL3 is involved in migration and in the production of proinflammatory cytokines. Furthermore, changes in the expression level of ORMDL3 are important in allergen-induced asthma pathologies. This review focuses on functional aspects of the ORMDL family proteins, which may serve as new therapeutic targets for the treatment of asthma and some other life-threatening diseases.

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Emerging concepts of ganglioside metabolism

Sandhoff

2018

FEBS Letters

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Gangliosides (GGs) are sialic acid-containing glycosphingolipids (GSLs) and major membrane components enriched on cellular surfaces. Biosynthesis of mammalian GGs starts at the cytosolic leaflet of endoplasmic reticulum (ER) membranes with the formation of their hydrophobic ceramide anchors. After intracellular ceramide transfer to Golgi and trans-Golgi network (TGN) membranes, anabolism of GGs, as well as of other GSLs, is catalyzed by membrane-spanning glycosyltransferases (GTs) along the secretory pathway. Combined activity of only a few promiscuous GTs allows for the formation of cell-type-specific glycolipid patterns. Following an exocytotic vesicle flow to the cellular plasma membranes, GGs can be modified by metabolic reactions at or near the cellular surface. For degradation, GGs are endocytosed to reach late endosomes and lysosomes. Whereas membrane-spanning enzymes of the secretory pathway catalyze GSL and GG formation, a cooperation of soluble glycosidases, lipases and lipid-binding cofactors, namely the sphingolipid activator proteins (SAPs), act as the main players of GG and GSL catabolism at intralysosomal luminal vesicles (ILVs).

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Expression of the ORMDLS, Modulators of Serine Palmitoyltransferase, Is Regulated by Sphingolipids in Mammalian Cells

Cited by 44 publications

References 29 publications

ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis

ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis

The role of ORMDL proteins, guardians of cellular sphingolipids, in asthma

Emerging concepts of ganglioside metabolism

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