ORMDL3

Official Full Name

ORMDL sphingolipid biosynthesis regulator 3

Organism

Homo sapiens

GeneID

94103

Background

Involved in ceramide metabolic process. Acts upstream of or within several processes, including negative regulation of B cell apoptotic process; negative regulation of ceramide biosynthetic process; and positive regulation of protein localization to nucleus. Located in endoplasmic reticulum. Part of serine palmitoyltransferase complex. [provided by Alliance of Genome Resources, Feb 2025]

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Detailed Information

The ER-resident transmembrane protein orosomucoid like 3 (ORMDL3) belongs to a novel evolutionarily conserved gene family which encodes transmembrane proteins located at the endoplasmic reticulum (ER) membrane. Breslow et al. found Orm proteins as negative regulators of sphingolipid synthesis and suggested that sphingolipid misregulation could contribute to the development of asthma. ORMDL3 has been found to alter ER Ca²⁺ concentration and facilitate the unfolded protein response (UPR), a process considered as an endogenous inducer of inflammation (Figure 1). ORMDL3 shows a wide distribution in different human tissues, being particularly high expression in cells that participate in the inflammatory response. Genetic variants on chromosome 17q21 locus were strongly associated with transcript levels of ORMDL3 in EBV-transformed lymphoblastoid cell lines from asthmatic children.

Figure 1. ORMDL3 facilitates the unfolded protein response (UPR).

ORMDL3 and sphingolipids

A role of orm proteins in the regulation of sphingolipid synthesis has been established in yeast for many years and recently has been demonstrated in human cells. ORMDL proteins act as negative regulators of sphingolipid synthesis by interacting with serine palmitoyl-coenzyme A transferase (SPT). SPT catalyzes the condensation of serine and palmitoyl-coenzyme A, the rate-limiting step of the de novo sphingolipid synthesis. The asthma-associated ORMDL3 SNPs are associated with higher expression of ORMDL. Knock-down of ORMDL1, 2, and 3 in mammalian cells increases ceramides, products of sphingolipid synthesis. Thus, asthma-associated SNPs are expected to negatively regulate SPT resulting in inhibited de novo sphingolipid synthesis.

ORMDL3 and asthma

None of the genes in the asthma-associated 17q21 region would have been associated with asthma without the unbiased GWAS approach. This approach is an opportunity to discover novel targets and pathomechanisms but has often been both a challenge and a curse for complex diseases. This is particularly true for ORMDL3. Up to date, 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 the regulator of sphingolipid synthesis. Since the asthma-associated SNPs result in increased cellular ORMDL3 protein expression, it would suggest that an asthma phenotype related to ORMDL3 should be associated with a gain-of-protein function. So far, the following mechanisms of how increased ORMDL3 could be related to asthma have been proposed (Figure 2): (i) ORMDL3 is involved in ER-mediated Ca²⁺ signaling and activation of the UPR, leading to epithelial cell remodeling via its effect on the sarco/endoplasmic reticulum CaATPase (SERCA) and (ii) ORDML3 influences sphingolipid metabolism to directly affect bronchial reactivity.

Figure 2. Proposed mechanisms for the role of ORMDL3 in asthma pathogenesis in an airway epithelial cell.

ORMDL3 is widely expressed in both fetal and adult mammalian tissues including lung epithelial cells. In mouse lungs, expression can be increased by various stimuli, such as allergens, lipopolysaccharides, and tobacco smoke. In lung epithelial cells, in vitro expression can be increased by interleukin-4 (IL-4) and interleukin-13 (IL-13) but not tumor necrosis factor-α. Interestingly, overexpression of ORMDL3 in airway epithelial cells activates activating transcription factor 6 (ATF6), one of the three signaling branches of the UPR in response to ER stress. This appears to be accompanied by increases in metalloproteases (ADAM-8, MMP-9), CC chemokines (CCL-20), CXC chemokines (CXCL-10, CXCL-11, IL-8), and oligoadenylate synthetase (OAS). These findings suggest that ORMDL3 is an allergen- and cytokine-inducible gene that could regulate the expression of chemokines, metalloproteinases, and OAS through activation of the UPR and thus may be linked to inflammatory and remodeling responses in asthma. Activation of the UPR has been implicated in other inflammatory and immune-related diseases other than asthma, such as inflammatory bowel disease, diabetes, and chronic obstructive pulmonary disease, as well as environmental stressors such as tobacco smoke, an important trigger for asthma exacerbations.

None of the current medications for asthma are disease modifying or curative. Despite tremendous efforts to find an underlying cause for asthma that can be targeted therapeutically, none of these have yet been successful. Remarkably though is the consistency with which the 17q21 locus and within it ORMDL3 has been associated with asthma. Without this approach, it is impossible that the genes in this region would have been primarily identified to be associated with asthma. It is becoming increasingly clear that this locus is associated with early-onset asthma and bronchial hyperreactivity, independent of allergic sensitization and wheezing phenotypes. Although the functional connection of altered ORMDL3 expression has not been made in humans, recent experimental data linking this protein’s effect on asthma to altered calcium homeostasis, airway remodeling, UPR, and sphingolipid synthesis opens new therapeutic targets for asthma at its basic mechanisms.

References:

Ono J G, et al. 17q21 locus and ORMDL3: an increased risk for childhood asthma. Pediatric Research, 2014, 75(2):165-170.
Jin R, et al. Characterization of a novel isoform of the human ORMDL3 gene. Cell & Tissue Research, 2011, 346(2):203-208.
Zhai W H, et al. Correlation between the genetic polymorphism of ORMDL3 gene and asthma risk: a meta-analysis. Genetics & Molecular Research Gmr, 2015, 14(2):7101-7112.
Jin R, et al. Mechanisms elevating ORMDL3 expression in recurrent wheeze patients: role of Ets-1, p300 and CREB. International Journal of Biochemistry & Cell Biology, 2012, 44(7):1174.
Carrerassureda A, et al. ORMDL3 modulates store-operated calcium entry and lymphocyte activation. Human Molecular Genetics, 2013, 22(3):519.
Löser S, et al. Pulmonary ORMDL3 is critical for induction of Alternaria-induced allergic airways disease. Journal of Allergy & Clinical Immunology, 2017, 139(5):1496-1507.

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