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)). Her...

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Published in:Human molecular genetics 2013-02, Vol.22 (3), p.519-530
Main Authors: Carreras-Sureda, Amado, Cantero-Recasens, Gerard, Rubio-Moscardo, Fanny, Kiefer, Kerstin, Peinelt, Christine, Niemeyer, Barbara A, Valverde, Miguel A, Vicente, Rubén
Format: Article
Language:English
Subjects:
Calcium
Calcium - metabolism
Calcium Signaling
Endoplasmic Reticulum - metabolism
HEK293 Cells
Humans
Interleukin-2 - metabolism
Ion Transport
Lymphocyte Activation
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mitochondria - metabolism
Orosomucoid - metabolism
Protein Transport
Receptors, Antigen, T-Cell - metabolism
T-Lymphocytes - metabolism
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Summary: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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/dds450