Orm family proteins mediate sphingolipid homeostasis

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. Sphingolipids in asthma Sphingolipids and their biosynthetic intermediates such as ceramide and sphingosine participate in key cellular processes including cell growth, membrane trafficking and inflammation. In recent genetic studies, mutations near the ORMDL3 gene were associated with childhood asthma. A functional genomic study in yeast cells now shows that Orm proteins function in sphingolipid homeostasis, and that alterations in this control result in misregulation of sphingolipid production and accumulation of toxic metabolites. This suggests that misregulation of sphingolipids may directly contribute to the development of asthma. Mutations near the ORMDL3 gene have been associated with childhood asthma. Here, in yeast, Orm proteins are shown to function in sphingolipid homeostasis; alterations in this control result in misregulation of sphingolipid production and accumulation of toxic metabolites. This raises the testable hypothesis that misregulation of sphingolipids may directly contribute to the development of asthma.