The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress.
Alterations of protein folding or Ca(2+) levels within the endoplasmic reticulum (ER) result in the unfolded-protein response (UPR), a process considered as an endogenous inducer of inflammation. Thereby, understanding how genetic factors modify UPR is particularly relevant in chronic inflammatory diseases such as asthma. Here we identified that ORMDL3, the only genetic risk factor recently associated to asthma in a genome wide study, alters ER-mediated Ca(2+) homeostasis and facilitates the UPR. Heterologous expression of human ER-resident transmembrane ORMDL3 protein increased resting cytosolic Ca(2+) levels and reduced ER-mediated Ca(2+) signaling, an effect reverted by co-expression with the sarco-endoplasmic reticulum Ca(2+) pump (SERCA). Increased ORMDL3 expression also promoted stronger activation of UPR transducing molecules and target genes while siRNA-mediated knock-down of endogenous ORMDL3 potentiated ER Ca(2+) release and attenuated the UPR. In conclusion, our findings are consistent with a model in which ORMDL3 binds and inhibits SERCA resulting in a reduced ER Ca(2+) concentration and increased UPR. Thus, we provide a first insight into the molecular mechanism explaining the association of ORMDL3 with proinflammatory diseases.
Cantero-Recasens
Gerard
G
Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Edifici PRBB, C/ Dr Aiguader 88, Barcelona, Spain.
Fandos
César
C
Rubio-Moscardo
Fanny
F
Valverde
Miguel A
MA
Vicente
Rubén
R
D001249:Asthma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D020013:Calcium Signaling; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology*; D020868:Gene Silencing; D006706:Homeostasis; D006801:Humans; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013312:Stress, Physiological; D056811:Unfolded Protein Response
D008565:Membrane Proteins; C464399:ORMDL3 protein, human; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases