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The short isoform of extended synaptotagmin-2 controls Ca(2+) dynamics in T cells via interaction with STIM1

Ca(2+) release-activated Ca(2+) (CRAC) channels elevate cytoplasmic Ca(2+) concentration, which is essential for T cell activation, differentiation and effector functions. T cell receptor stimulation induces depletion of the endoplasmic reticulum (ER) Ca(2+) stores, which is sensed by stromal intera...

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Detalles Bibliográficos
Autores principales: Woo, Jin Seok, Sun, Zuoming, Srikanth, Sonal, Gwack, Yousang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468131/
https://www.ncbi.nlm.nih.gov/pubmed/32879390
http://dx.doi.org/10.1038/s41598-020-71489-7
Descripción
Sumario:Ca(2+) release-activated Ca(2+) (CRAC) channels elevate cytoplasmic Ca(2+) concentration, which is essential for T cell activation, differentiation and effector functions. T cell receptor stimulation induces depletion of the endoplasmic reticulum (ER) Ca(2+) stores, which is sensed by stromal interaction molecule 1 (STIM1). STIM1 translocates to the ER-plasma membrane (PM) junctions to interact with ORAI1, the pore subunit of the CRAC channels. Here, we show that two members of the extended synaptotagmin (E-Syt) family, E-Syt1, and the short isoform of E-Syt2 (E-Syt2S), contribute to activation of CRAC channels in T cells. Knockdown or deletion of both ESYT1 and ESYT2 reduced store-operated Ca(2+) entry (SOCE) and ORAI1-STIM1 clustering in Jurkat T cells. Further, depletion of E-Syts in primary T cells decreased Ca(2+) entry and cytokine production. While the ER-PM junctions were reduced in both HeLa and Jurkat T cells deleted for ESYT1 and ESYT2, SOCE was impaired only in Jurkat T cells, suggesting that the membrane-tethering function of E-Syts is distinct from their role in SOCE. Mechanistically, E-Syt2S, the predominant isoform of E-Syt2 in T cells, recruited STIM1 to the junctions via a direct interaction. This study demonstrates a membrane-tethering-independent role of E-Syts in activation of CRAC channels in T cells.