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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.

The short isoform of extended synaptotagmin-2 controls Ca2+ dynamics in T cells via interaction with STIM1