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bioRxiv · 10.1101/2021.02.03.429577

S-acylation targets ORAI1 channels to lipid rafts for efficient Ca2+ signaling by T cell receptors at the immune synapse

Carreras-Sureda, A.·Abrami, L.·JI-Hee, K.·Frieden, M.·Didier, M.·van der Goot, F. G.·Demaurex, N.
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Abstract

Efficient immune responses require Ca2+ fluxes across ORAI1 channels during engagement of T cell receptors (TCR) at the immune synapse (IS) between T cells and antigen presenting cells. Here, we show that ZDHHC20-mediated S-acylation of the ORAI1 channel at residue Cys143 is required for TCR assembly and signaling at the IS. Cys143 mutations reduced ORAI1 currents and store-operated Ca2+ entry in HEK-293 cells and nearly abrogated long-lasting Ca2+ elevations, NFATC1 translocation, and IL-2 secretion evoked by TCR engagement in Jurkat T cells. The acylation-deficient channel had reduced mobility in lipids, accumulated in cholesterol-poor domains, formed tiny clusters, failed to reach the IS and unexpectedly also prevented TCR recruitment to the IS. Our results establish S-acylation as a critical regulator of ORAI1 channel assembly and function at the IS and reveal that local Ca2+ fluxes are required for TCR recruitment to the synapse.

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Carreras-Sureda, A., Abrami, L., JI-Hee, K., Frieden, M., Didier, M., van der Goot, F. G., Demaurex, N.. 2021-02-04. S-acylation targets ORAI1 channels to lipid rafts for efficient Ca2+ signaling by T cell receptors at the immune synapse. https://doi.org/10.1101/2021.02.03.429577

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