ORMDL3 modulates store-operated calcium entry and lymphocyte activation

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.