ORMDL3 modulates store-operated calcium entry and lymphocyte activation.

Carreras-Sureda, Amado; Cantero-Recasens, Gerard; Rubio-Moscardo, Fanny; Kiefer, Kerstin; Peinelt, Christine; Niemeyer, Barbara A; Valverde, Miguel A; Vicente, Rubén (2013). ORMDL3 modulates store-operated calcium entry and lymphocyte activation. Human molecular genetics, 22(3), pp. 519-530. Oxford University Press 10.1093/hmg/dds450

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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.

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