NKD2 mediates stimulation-dependent ORAI1 trafficking to augment Ca2+ entry in T cells

Sustained activation of the Ca2+-release-activated Ca2+ (CRAC) channel is pivotal for effector T cell responses. The mechanisms underlying this sustainability remain poorly understood. We find that plasma membrane localization of ORAI1 the pore subunit of CRAC channels, is limited in effector T cells, with a significant fraction trapped in intracellular vesicles. From a targeted screen, we identify an essential component of ORAI1(+) vesicles, naked cuticle homolog 2 (NKD2). Mechanistically, NKD2, an adaptor molecule activated by signaling pathways downstream of T cell receptors, orchestrates trafficking and insertion of ORAI1(+) vesicles to the plasma membrane. Together, our findings suggest that T cell receptor (TCR)-stimulation-dependent insertion of ORAI1 into the plasma membrane is essential for sustained Ca2+ signaling and cytokine production in T cells.

Automated summary

In effector T cells, the pore subunit of CRAC channels, ORAI1, is limited in plasma membrane localization with a significant fraction trapped in intracellular vesicles. NKD2, an essential component of ORAI1(+) vesicles activated by signaling pathways downstream of T cell receptors, orchestrates trafficking and insertion of ORAI1(+) vesicles to the plasma membrane. T cell receptor (TCR)-stimulation-dependent insertion of ORAI1 into the plasma membrane is essential for sustained calcium signaling and cytokine production in T cells.