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S-acylation by ZDHHC20 targets ORAI1 channels to lipid rafts for efficient Ca2+ signaling by Jurkat T cell receptors at the immune synapse.


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 promotes TCR recruitment 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 remained in cholesterol-poor domains upon enforced ZDHHC20 expression and was recruited less efficiently to the IS along with actin and TCR. Our results establish S-acylation as a critical regulator of ORAI1 channel trafficking and function at the IS and reveal that ORAI1 S-acylation enhances TCR recruitment to the synapse.

SUBMITTER: Carreras-Sureda A 

PROVIDER: S-EPMC8683079 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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S-acylation by ZDHHC20 targets ORAI1 channels to lipid rafts for efficient Ca<sup>2+</sup> signaling by Jurkat T cell receptors at the immune synapse.

Carreras-Sureda Amado A   Abrami Laurence L   Ji-Hee Kim K   Wang Wen-An WA   Henry Christopher C   Frieden Maud M   Didier Monica M   van der Goot F Gisou FG   Demaurex Nicolas N  

eLife 20211216


Efficient immune responses require Ca<sup>2+</sup> 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 promotes TCR recruitment and signaling at the IS. Cys143 mutations reduced ORAI1 currents and store-operated Ca<sup>2+</sup> entry in HEK-293 cells and nearly abrogated long-lasting Ca<sup>2+</sup> elevations, NFATC1  ...[more]

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