Abstract
CRAC channels enable calcium entry from the extracellular space in response to a variety of stimuli and are crucial for gene expression and granule exocytosis in lymphocytes. Here we find that Syntaxin11, a Q-SNARE, associated with FHLH4 disease in human patients, directly binds Orai1, the pore forming subunit of CRAC channels. Syntaxin11 depletion strongly inhibited SOCE, CRAC currents, IL-2 expression and cytotoxicity in cell lines and FHLH4 patient T lymphocytes. Constitutively active H134 Orai1 mutant completely reconstituted calcium entry in Syntaxin11 depleted cells and the defects of granule exocytosis as well as gene expression could be bypassed by ionomycin induced calcium influx in FHLH4 T lymphocytes. Our data reveal a Syntaxin11 induced pre-activation state of Orai which is necessary for its subsequent coupling and gating by the endoplasmic reticulum resident Stim protein. We propose that ion channel regulation by specific SNAREs is a primary and conserved function which may have preceded their role in vesicle fusion.