Orm family proteins mediate sphingolipid homeostasis.
Nature
; 463(7284): 1048-53, 2010 Feb 25.
Article
em En
| MEDLINE
| ID: mdl-20182505
ABSTRACT
Despite the essential roles of sphingolipids both as structural components of membranes and critical signalling molecules, we have a limited understanding of how cells sense and regulate their levels. Here we reveal the function in sphingolipid metabolism of the ORM genes (known as ORMDL genes in humans)-a conserved gene family that includes ORMDL3, which has recently been identified as a potential risk factor for childhood asthma. Starting from an unbiased functional genomic approach in Saccharomyces cerevisiae, we identify Orm proteins as negative regulators of sphingolipid synthesis that form a conserved complex with serine palmitoyltransferase, the first and rate-limiting enzyme in sphingolipid production. We also define a regulatory pathway in which phosphorylation of Orm proteins relieves their inhibitory activity when sphingolipid production is disrupted. Changes in ORM gene expression or mutations to their phosphorylation sites cause dysregulation of sphingolipid metabolism. Our work identifies the Orm proteins as critical mediators of sphingolipid homeostasis and raises the possibility that sphingolipid misregulation contributes to the development of childhood asthma.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Saccharomyces cerevisiae
/
Esfingolipídeos
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Família Multigênica
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Proteínas de Saccharomyces cerevisiae
/
Homeostase
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Nature
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Estados Unidos