Orm1 and Orm2 are conserved endoplasmic reticulum membrane proteins regulating lipid homeostasis and protein quality control

Abstract

Yeast members of the ORMDL family of endoplasmic reticulum (ER) membrane proteins play a central role in lipid homeostasis and protein quality control. In the absence of yeast Orm1 and Orm2, accumulation of long chain base, a sphingolipid precursor, suggests dysregulation of sphingolipid synthesis. Physical interaction between Orm1 and Orm2 and serine palmitoyltransferase, responsible for the first committed step in sphingolipid synthesis, further supports a role for the Orm proteins in regulating sphingolipid synthesis. Phospholipid homeostasis is also affected in orm1 Δ orm2 Δ cells: the cells are inositol auxotrophs with impaired transcriptional regulation of genes encoding phospholipid biosynthesis enzymes. Strikingly, impaired growth of orm1 Δ orm2 Δ cells is associated with constitutive unfolded protein response, sensitivity to stress, and slow ER-to-Golgi transport. Inhibition of sphingolipid synthesis suppresses orm1 Δ orm2 Δ phenotypes, including ER stress, suggesting that disrupted sphingolipid homeostasis accounts for pleiotropic phenotypes. Thus, the yeast Orm proteins control membrane biogenesis by coordinating lipid homeostasis with protein quality control.

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

“…A link between ORM genes and sphingolipid metabolism was first established for yeast ORM1 and ORM2 by systematic measurement of genetic interactions . These functional genomic data suggested that Orm1/2 negatively regulate sphingolipid production, and consistent with this prediction, deletion of ORM1/2 leads to toxic accumulation of sphingolipids, whereas ORM1/2 overexpression reduces sphingolipid levels Han et al 2010). Orm proteins regulate sphingolipid metabolism by forming a multiprotein complex with SPT termed the SPOTS complex (named for its components serine palmitoyltransferase, Orm1/2, the SPT accessory subunit Tsc3, and the phosphoinositide phosphatase Sac1) .…”

“…Given the broad functions of sphingolipids, it is clear that many other cellular activities depend on sphingolipids; likewise, many other metabolic and secretory pathway processes influence and regulate sphingolipid metabolism. For instance, disruption of sphingolipid metabolism induces the unfolded protein response (UPR), whereas sphingolipid genes such as ORM2 are themselves UPR targets (Travers et al 2000;Spassieva et al 2009;Han et al 2010;Liu et al 2012). Similarly, heat shock induces LCB and ceramide production, and sphingolipids in turn promote thermotolerance (for a review, see Dickson et al 2006).…”

“…Genetic or pharmacologic inhibition of sphingolipid synthesis blocks cell proliferation in organisms ranging from mammals to fungi (Buede et al 1991;Miyake et al 1995;Hanada et al 1998;Yamashita et al 1999;Hojjati et al 2005). Conversely, an excess of sphingolipids is also toxic, leading to ER stress and disruption of calcium homeostasis (LloydEvans et al 2008;Han et al 2010). Increased levels of ceramides or LCB-Ps cause lethality in yeast (Schorling et al 2001;Zhang et al 2001), and a number of human lysosomal storage diseases, including Tay-Sachs disease, Niemann-Pick disease, and Gaucher disease, are attributable to mutations that block sphingolipid breakdown (Schulze and Sandhoff 2011).…”

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

“…Until recently, little was known about its overall cellular function in mammalian cells, as most of its function had been studied in yeast. There, ORMDL functions as regulator of sphingolipid synthesis (24). 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.…”

“…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).…”