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Transcription factor NF-κB regulates expression of pore-forming Ca2+ channel unit, Orai1, and its activator, STIM1,

Anja Eylenstein1, Sebastian Schmidt, Shuchen Gu

  • 1Department of Physiology, University of Tübingen, Gmelinstrasse 5, D-72076 Tübingen, Germany.

The Journal of Biological Chemistry
|November 24, 2011
PubMed

Insights

Serum and glucocorticoid-inducible kinase (SGK1) regulates Orai1/STIM1 transcription via NF-κB signaling, impacting calcium entry and cell migration. This study elucidates a novel genomic regulatory pathway involving SGK1, NF-κB, and calcium channel components.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Immunology

Background:

  • Serum and glucocorticoid-inducible kinase 1 (SGK1) modulates Orai1 activity, a key component of store-operated calcium entry, influencing calcium-dependent cellular processes.
  • SGK1 is also known to regulate the transcription factor nuclear factor kappa B (NF-κB).

Purpose of the Study:

  • To investigate the role of SGK1 in regulating the transcription of Orai1 and STIM1, the sensor for Orai1 activation.
  • To elucidate the signaling pathway linking SGK1, NF-κB, and the expression of Orai1 and STIM1.

Main Methods:

  • Gene expression analysis in SGK1 knockout and wild-type mast cells.
  • Transfection studies in HEK293 cells with active/inactive SGK1 and NF-κB subunits.
  • Inhibition of NF-κB signaling using Wogonin.
  • Luciferase reporter assays and chromatin immunoprecipitation to identify NF-κB binding sites.
  • Assessment of store-operated calcium entry and cell migration.

Main Results:

  • SGK1 deficiency reduced Orai1 and STIM1 transcript levels, while SGK1 overexpression increased them.
  • NF-κB activation was crucial for SGK1-mediated Orai1/STIM1 transcription, as inhibition or silencing of NF-κB blocked these effects.
  • NF-κB binding sites were identified in the promoter regions of Orai1 and STIM1.
  • Modulation of Orai1/STIM1 expression by SGK1 and NF-κB directly affected store-operated calcium entry and cell migration.

Conclusions:

  • SGK1 exerts powerful genomic control over Orai1 and STIM1 expression through an NF-κB-dependent signaling pathway.
  • This SGK1-NF-κB axis represents a significant regulatory mechanism for calcium homeostasis and cell migratory functions.

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