Orm family proteins mediate sphingolipid homeostasis

Abstract

Despite the essential roles of sphingolipids as both 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/ORMDL genes, 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, 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 contribute to acetic acid resistance in Zygosaccharomyces bailii

“…The use of myriocin is well established, and previous studies have demonstrated its ability to decrease the fraction of sphingolipids in various cell systems, including yeast (Breslow et al, 2010; Huang et al, 2012; Shimobayashi et al, 2013). …”

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

“…A role of orm proteins in the regulation of sphingolipid synthesis has been well established in yeast for many years (24,28,(37)(38)(39) and has recently been demonstrated in human cells (40,41). ORMDL proteins act as negative regulators of sphingolipid synthesis by interacting with serine palmitoyl-coenzyme A transferase (SPT) (38).…”

“…ORMDL proteins act as negative regulators of sphingolipid synthesis by interacting with serine palmitoyl-coenzyme A transferase (SPT) (38). SPT catalyzes the condensation of serine and palmitoyl-coenzyme A, the rate-limiting step of the de novo sphingolipid synthesis (Figure 2).…”

“…The regulation of sphingolipid metabolism is incompletely understood and likely complex through multiple interconnected mechanisms (37). Although de novo sphingolipid synthesis may only play a minor contribution to the total cellular sphingolipid pool (46), homeostatic regulators of de novo synthesis such as ORMDL stabilize cellular sphingolipid levels in the face of external perturbations (37,38,47). Previous studies linking asthma to sphingolipids have been centered on inflammatory and allergic mechanisms related to the sphingolipid mediator S1P (48)(49)(50)(51)(52)(53).…”

Protein kinase Gin4 negatively regulates flippase function and controls plasma membrane asymmetry

“…Ypk1 phosphorylates and inactivates Orm1 and Orm2 (Roelants et al, 2011), two major negative regulators of SPT (Breslow et al, 2010); hence, elevated Fpk1-mediated feedback inhibition of Ypk1 would be expected to impede all sphingolipid biosynthesis. However, total sphingolipid levels were not significantly altered in cells expressing Fpk1 11A compared with wild-type or fpk1 fpk2 cells (Fig.…”