title: ORMDL3 modulates store-operated calcium entry and lymphocyte activation.
abstract: T lymphocytes rely on a Ca(2+) signal known as store-operated calcium entry (SOCE) for their activation. This Ca(2+) signal is generated by activation of a T-cell receptor, depletion of endoplasmic reticulum (ER) Ca(2+) stores and activation of Ca(2+) release-activated Ca(2+) currents (I(CRAC)). Here, we report that the ER protein orosomucoid like 3 (ORMDL3), the product of the ORMDL3 gene associated with several autoimmune and/or inflammatory diseases, negatively modulates I(CRAC), SOCE, nuclear factor of activated T cells nuclear translocation and interleukin-2 production. ORMDL3 inhibits the Ca(2+) influx mechanism at the outer mitochondrial membrane, resulting in a Ca(2+)-dependent inhibition of I(CRAC) and reduced SOCE. The effect of ORMDL3 could be mimicked by interventions that decreased mitochondrial Ca(2+) influx and reverted by buffering of cytosolic Ca(2+) or activation of mitochondrial Ca(2+) influx. In conclusion, ORMDL3 modifies key steps in the process of T-lymphocyte activation, providing a functional link between the genetic associations of the ORMDL3 gene with autoimmune and/or inflammatory diseases.
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain.
authors.forename: Amado
authors.initials: A
authors.lastname: Carreras-Sureda
authors.forename: Gerard
authors.initials: G
authors.lastname: Cantero-Recasens
authors.forename: Fanny
authors.initials: F
authors.lastname: Rubio-Moscardo
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kiefer
authors.forename: Christine
authors.initials: C
authors.lastname: Peinelt
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Niemeyer
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Valverde
authors.forename: Rubén
authors.initials: R
authors.lastname: Vicente
mesh_terms: D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D017136:Ion Transport; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D009961:Orosomucoid / Q000378:metabolism; D021381:Protein Transport; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D007376:Interleukin-2; D008565:Membrane Proteins; C464399:ORMDL3 protein, human; D009961:Orosomucoid; D011948:Receptors, Antigen, T-Cell; D002118:Calcium