Identification of the Orm family of proteins as critical mediators of sphingolipid homeostasis

Although recent studies have shed light on the critical roles of sphingolipids both as structural components of membranes and critical signaling molecules, how cells sense and regulate the levels of sphingolipids has remained a mystery. We found that members of the highly conserved but previously uncharacterized Orm protein family inhibit the first and rate-limiting step of de novo sphingolipid production. Moreover, the activity of Orm proteins is dynamically regulated by a key feedback loop: when sphingolipid synthesis is disrupted, Orm proteins are inactivated by phosphorylation, thus providing cells with an elegant mechanism to couple sphingolipid production to metabolic demand.

Our findings are of particular interest in light of the recent identification of a major genetic risk factor for asthma near the locus of the human ORM gene homolog ORMDL3. Polymorphisms which alter ORMDL3 expression account for up to ~20% of childhood asthma cases and have also been implicated in other inflammation-based diseases such as Type I diabetes. Thus, our finding that alterations in ORM gene activity profoundly affect sphingolipid metabolism raises the testable hypothesis that misregulation of sphingolipids contributes directly to the pathogenesis of asthma. We are now extending our initial studies to define the mechanism by which Ormdl proteins are regulated in mammalian cells. Recent progress in identifying upstream components of the yeast phosphorylation feedback pathway will guide these efforts and may also enable us to define a molecular sensor of sphingolipid levels. Thus, our work on Orm family proteins promises to inform a fundamental question in cell biology and may also reveal novel roles for sphingolipids in inflammatory diseases.