ORMDL3 modulates store-operated calcium entry and lymphocyte activation

Abstract

T lymphocytes rely on a Ca²⁺ signal known as store-operated calcium entry (SOCE) for their activation. This Ca²⁺ signal is generated by activation of a T-cell receptor, depletion of endoplasmic reticulum (ER) Ca²⁺ stores and activation of Ca²⁺ release-activated Ca²⁺ 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 Ca²⁺ influx mechanism at the outer mitochondrial membrane, resulting in a Ca²⁺-dependent inhibition of I_CRAC and reduced SOCE. The effect of ORMDL3 could be mimicked by interventions that decreased mitochondrial Ca²⁺ influx and reverted by buffering of cytosolic Ca²⁺ or activation of mitochondrial Ca²⁺ 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.