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A longer isoform of Stim1 is a negative SOCE regulator but increases cAMP‐modulated NFAT signaling
Author(s) -
Knapp Mona L,
Alansary Dalia,
Poth Vanessa,
Förderer Kathrin,
Sommer Frederik,
Zimmer David,
Schwarz Yvonne,
Künzel Nicolas,
Kless Achim,
Machaca Khaled,
Helms Volkhard,
Mühlhaus Timo,
Schroda Michael,
Lis Annette,
Niemeyer Barbara A
Publication year - 2021
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202153135
Subject(s) - nfat , stim1 , microbiology and biotechnology , orai1 , crosstalk , alternative splicing , regulator , activator (genetics) , biology , chemistry , transcription factor , gene isoform , endoplasmic reticulum , biochemistry , receptor , physics , gene , optics
Alternative splicing is a potent modifier of protein function. Stromal interaction molecule 1 (Stim1) is the essential activator of store‐operated Ca 2+ 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 I CRAC, 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.