Impaired Sphingolipid Synthesis in the Respiratory Tract Induces Airway Hyperreactivity

Worgall, Tilla S.; Veerappan, Arul; Sung, Biin; Kim, Benjamin I.; Weiner, Evan; Bholah, Reshma; Silver, Randi B.; Jiang, Xian‐Cheng; Worgall, Stefan

doi:10.1126/scitranslmed.3005765

Cited by 100 publications

(116 citation statements)

References 55 publications

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“…A recent study from our laboratories suggest that impaired de novo sphingolipid synthesis leads to airway hyperreactivity in mouse lungs and both human and murine bronchial rings. In addition, we observed altered magnesium homeostasis and contractile response to magnesium (27). SPT activity in the lung was decreased using myriocin, a specific inhibitor of SPT, or using a genetic model of SPT-haploinsufficient mice.…”

Section: Ormdl3 and Sphingolipidsmentioning

confidence: 90%

“…Since the asthmaassociated SNPs lead to increased cellular ORMDL3 protein expression, it would suggest that an asthma phenotype related to ORMDL3 should be associated with a gain-of-protein function. To date, the following mechanisms of how increased ORMDL3 could be related to asthma have been proposed (Figure 1): (i) ORMDL3 is involved in ER-mediated Ca 2+ signaling and activation of the unfolded protein response (UPR), leading to epithelial cell remodeling through its effect on the sarco/endoplasmic reticulum CaATPase (SERCA) (25,26) and (ii) ORDML3 influences sphingolipid metabolism to directly affect bronchial reactivity (27).…”

Section: Linking Gene(s) To Function(s)mentioning

confidence: 99%

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17q21 locus and ORMDL3: an increased risk for childhood asthma

Ono

Worgall

2013

Pediatr Res

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Section: Ormdl3 and Sphingolipidsmentioning

confidence: 90%

Section: Linking Gene(s) To Function(s)mentioning

confidence: 99%

17q21 locus and ORMDL3: an increased risk for childhood asthma

Ono

Worgall

2013

Pediatr Res

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“…It might be expected that overexpression of ORMDL3 would lead to suppression of SPT. Indeed a suppression of sphingolipid synthesis has been proposed to be the underlying biochemical effect which elevates the risk of asthma in individuals carrying the risk allele of ORMDL3 ( 8,18 ). To test this directly, we transiently transfected HeLa cells with ORMD3 (from mouse) and established, by lentiviral infection, two HBEC cell lines stably expressing elevated levels of human ORMDL3 ( Fig.…”

Section: Overexpression Of Ormdl3 Does Not Suppress De Novo Sphingolimentioning

confidence: 99%

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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“…Mice overexpressing ORMDL3 showed lung airway remodeling characteristic of asthma, increased area of peribronchial smooth muscles, increased peribronchial fibrosis, increased lung collagen, and mucus expression (4,67). Mice treated with myriocin, which causes decreased sphingosine synthesis, exhibited airway hyper-responsiveness (AHR) to inhaled methacholine (102). On the other hand, no AHR was observed in myriocin-treated mice in a recent study by Oyeniran and coworkers (67).…”

Section: The Role Of Ormdls In Immune Response Regulationmentioning

confidence: 96%

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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Impaired Sphingolipid Synthesis in the Respiratory Tract Induces Airway Hyperreactivity

Cited by 100 publications

References 55 publications

17q21 locus and ORMDL3: an increased risk for childhood asthma

17q21 locus and ORMDL3: an increased risk for childhood asthma

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

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

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