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

• Published in: Cell reports (Cambridge) 2021-08, Vol.36 (8), p.109603-109603, Article 109603
• Main Authors: Wu, Beibei, Woo, Jin Seok, Vila, Pamela, Jew, Marcus, Leung, Jennifer, Sun, Zuoming, Srikanth, Sonal, Gwack, Yousang
• Format: Article
• Language: English
• Subjects: ORAI1, STIM1, T cell receptor signaling, NKD2, CRAC channels, effector T cells, store-operated calcium entry, intracellular vesicles
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109603

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. [Display omitted] •Sustained activation of the CRAC channel is pivotal for effector T cell responses•Plasma membrane localization of ORAI1 is limited in effector T cells•NKD2 is an adaptor molecule activated by signaling pathways downstream of TCRs•NKD2 orchestrates trafficking of ORAI1+ vesicles to the plasma membrane Wu et al. address the mechanism underlying sustained activation of the Ca2+-release-activated Ca2+ (CRAC) channel that is pivotal for effector T cell responses. They report that NKD2-mediated insertion of ORAI1 into the plasma membrane after TCR stimulation is essential for sustained Ca2+ signaling and cytokine production in T cells.