2. Academic Validation
  3. A longer isoform of Stim1 is a negative SOCE regulator but increases cAMP-modulated NFAT signaling

A longer isoform of Stim1 is a negative SOCE regulator but increases cAMP-modulated NFAT signaling

  • EMBO Rep. 2022 Feb 3;23(3):e53135. doi: 10.15252/embr.202153135.
Mona L Knapp 1,  Dalia Alansary 1,  Vanessa Poth 1,  Kathrin Förderer 1,  Frederik Sommer 2,  David Zimmer 3,  Yvonne Schwarz 4,  Nicolas Künzel 5,  Achim Kless 6,  Khaled Machaca 7,  Volkhard Helms 5,  Timo Mühlhaus 3,  Michael Schroda 2,  Annette Lis 8,  Barbara A Niemeyer 1
Affiliations

Affiliations

  • 1 Molecular Biophysics, Saarland University, Homburg, Germany.
  • 2 Molecular Biotechnology and Systems Biology, TU Kaiserslautern, Kaiserslautern, Germany.
  • 3 Computational Systems Biology, TU Kaiserslautern, Kaiserslautern, Germany.
  • 4 Molecular Neurophysiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Germany.
  • 5 Center for Bioinformatics, Saarland University, Saarbruecken, Germany.
  • 6 Grünenthal Innovation, Drug Discovery Technologies, Grünenthal GmbH, Aachen, Germany.
  • 7 Weill Cornell Medicine, Doha, Qatar.
  • 8 Biophysics, Saarland University, Homburg, Germany.
PMID: 34942054 DOI: 10.15252/embr.202153135
Abstract

Alternative splicing is a potent modifier of protein function. Stromal interaction molecule 1 (Stim1) is the essential activator of store-operated CA2+ entry (SOCE) triggering activation of transcription factors. Here, we characterize Stim1A, a splice variant with an additional 31 amino acid domain inserted in frame within its cytosolic domain. Prominent expression of exon A is found in astrocytes, heart, kidney, and testes. Full-length Stim1A functions as a dominant-negative regulator of SOCE and ICRAC, facilitating sequence-specific fast calcium-dependent inactivation and destabilizing gating of Orai channels. Downregulation or absence of native Stim1A results in increased SOCE. Despite reducing SOCE, Stim1A leads to increased NFAT translocation. Differential proteomics revealed an interference of Stim1A with the cAMP-SOCE crosstalk by altered modulation of phosphodiesterase 8 (PDE8), resulting in reduced cAMP degradation and increased PIP5K activity, facilitating NFAT activation. Our study uncovers a hitherto unknown mechanism regulating NFAT activation and indicates that cell-type-specific splicing of Stim1 is a potent means to regulate the NFAT signalosome and cAMP-SOCE crosstalk.

Keywords

NFAT; Orai; PDE8; PIP2; PIP5K.

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