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ORMDL3 modulates store-operated calcium entry and lymphocyte activation.

Amado Carreras-Sureda1, Gerard Cantero-Recasens, Fanny Rubio-Moscardo

  • 1Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain.

Human Molecular Genetics
|October 27, 2012
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Summary

The ER protein ORMDL3 negatively regulates T lymphocyte activation by inhibiting store-operated calcium entry (SOCE). This finding links ORMDL3 gene variants to autoimmune and inflammatory diseases.

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Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • T lymphocyte activation critically depends on store-operated calcium entry (SOCE), a calcium signal initiated by T-cell receptor activation.
  • The endoplasmic reticulum (ER) protein ORMDL3 is encoded by a gene associated with autoimmune and inflammatory diseases.

Purpose of the Study:

  • To investigate the role of ORMDL3 in T lymphocyte activation and its modulation of calcium signaling.
  • To establish a functional link between ORMDL3, T cell activation, and autoimmune/inflammatory disease associations.

Main Methods:

  • Studied the effect of ORMDL3 on calcium release-activated calcium currents (I(CRAC)) and SOCE in T lymphocytes.
  • Assessed the impact of ORMDL3 on nuclear factor of activated T cells (NFAT) nuclear translocation and interleukin-2 production.
  • Investigated the mechanism of ORMDL3 inhibition, focusing on mitochondrial calcium influx.

Main Results:

  • ORMDL3 negatively modulates I(CRAC), SOCE, NFAT nuclear translocation, and IL-2 production in T lymphocytes.
  • ORMDL3 inhibits calcium influx at the outer mitochondrial membrane, leading to calcium-dependent inhibition of I(CRAC) and reduced SOCE.
  • Interventions decreasing mitochondrial calcium influx mimicked ORMDL3's effect, while buffering cytosolic calcium or activating mitochondrial calcium influx reversed it.

Conclusions:

  • ORMDL3 acts as a negative regulator of key T lymphocyte activation steps, including calcium signaling.
  • The study provides a functional mechanism connecting the ORMDL3 gene, T cell activation, and its genetic association with autoimmune/inflammatory diseases.