Deregulation of ORMDL3 expression induces stress responses and modulates repair pathways

The asthma-susceptibility gene ORMDL3 is an ER transmembrane protein previously associated with sphingolipid metabolism, the unfolded protein response, Ca2+ homeostasis, T-cell activation, and antiviral responses. However, the functional relevance of ORMDL3 in asthma pathogenesis remains elusive. Using the fruit fly Drosophila melanogaster as a model, we mimicked the situation found in patients at risk for asthma by increasing the expression of ormdl, the sole Drosophila homolog of ORMDL3, in the airway epithelium. Although ormdl overexpression did not overtly affect epithelial integrity, it increased the susceptibility to airborne stressors, such as cigarette smoke and hypoxia. When confronted by daily doses of cigarette smoke, flies overexpressing ormdl in the airway epithelia had a significantly shortened lifespan compared to matched controls. Moreover, these animals exhibited a much stronger behavioral response to hypoxia, and signaling systems such as the unfolded protein response and the TOR/PI3K pathway lost their ability to react to this stressor. In addition, overexpression of ormdl in the airways drastically reduced the output of signaling pathways associated with repair mechanisms, including EGFR and Notch signaling. These molecular changes were accompanied by changes in the lipid profile that resembled the situation observed in asthmatic airways. On the basis of these findings, we conclude that ORMDL proteins increase the stress status of the airway epithelium, which increases susceptibility to stress factors and increases the probability of developing asthma.