Store-operated Ca²⁺ entry (SOCE) encodes a range of cellular responses downstream of Ca²⁺ influx through the SOCE channel Orai1. Orai1 recycles at the plasma membrane (PM), with ~40% of the total Orai1 pool residing at the PM at steady state. The mechanisms regulating Orai1 recycling remain poorly understood. We map the domains in Orai1 that are required for its trafficking to and recycling at the PM. We further identify, using biochemical and proteomic approaches, the CCT [chaperonin-containing TCP-1 (T-complex protein 1)] chaperonin complex as a novel regulator of Orai1 recycling by primarily regulating Orai1 endocytosis. We show that Orai1 interacts with CCT through its intracellular loop and that inhibition of CCT-Orai1 interaction increases Orai1 PM residence. This increased residence is functionally significant as it results in prolonged Ca²⁺ signaling, early formation of STIM1-Orai1 puncta, and more rapid activation of NFAT (nuclear factor of activated T cells) downstream of SOCE. Therefore, the CCT chaperonin is a novel regulator of Orai1 trafficking and, as such, a modulator of Ca²⁺ signaling and effector activation kinetics.

中文翻译：

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CCT伴侣蛋白是通过调节Orai1转运来调节Ca2 +信号的新型调节剂。

存储操作的Ca ²⁺条目（SOCE）编码Ca ²⁺下游的一系列细胞反应通过SOCE频道Orai1流入。Orai1在质膜（PM）处循环，约有40％的Orai1池在稳态时位于PM处。调节Orai1回收的机制仍然知之甚少。我们映射了Orai1中将其运输到PM并进行回收所需的域。我们进一步使用生化和蛋白质组学方法，通过主要调节Orai1内吞作用，将CCT [含伴侣蛋白的TCP-1（T-复合蛋白1）]伴侣蛋白复合物作为Orai1回收的新型调节剂。我们显示，Orai1通过其细胞内环与CCT相互作用，并且对CCT-Orai1相互作用的抑制增加了Orai1 PM的驻留。滞留时间的增加在功能上很重要，因为它会导致Ca ²⁺延长信号，STIM1-Orai1点的早期形成以及SOCE下游NFAT（活化T细胞的核因子）的更快活化。因此，CCT伴侣蛋白是Orai1交易的新型调节剂，因此是Ca ²⁺信号传导和效应子激活动力学的调节剂。