Department of Biochemistry, Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
Department of Biochemistry, Technion Integrated Cancer Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
J Cell Biol. 2021 Dec 6;220(12). doi: 10.1083/jcb.202104007. Epub 2021 Oct 27.
Store-operated calcium entry (SOCE) through the Ca2+ release-activated Ca2+ (CRAC) channel is a central mechanism by which cells generate Ca2+ signals and mediate Ca2+-dependent gene expression. The molecular basis for CRAC channel regulation by the SOCE-associated regulatory factor (SARAF) remained insufficiently understood. Here we found that following ER Ca2+ depletion, SARAF facilitates a conformational change in the ER Ca2+ sensor STIM1 that relieves an activation constraint enforced by the STIM1 inactivation domain (ID; aa 475-483) and promotes initial activation of STIM1, its translocation to ER-plasma membrane junctions, and coupling to Orai1 channels. Following intracellular Ca2+ rise, cooperation between SARAF and the STIM1 ID controls CRAC channel slow Ca2+-dependent inactivation. We further show that in T lymphocytes, SARAF is required for proper T cell receptor evoked transcription. Taking all these data together, we uncover a dual regulatory role for SARAF during both activation and inactivation of CRAC channels and show that SARAF fine-tunes intracellular Ca2+ responses and downstream gene expression in cells.
钙库操纵的钙内流（SOCE）通过钙释放激活钙（CRAC）通道是细胞产生钙信号和介导钙依赖性基因表达的核心机制。SOCE 相关调节因子（SARAF）调节 CRAC 通道的分子基础仍知之甚少。在这里，我们发现 ER 钙耗竭后，SARAF 促进 ER 钙传感器 STIM1 的构象变化，解除 STIM1 失活域（ID；aa475-483）施加的激活约束，并促进 STIM1 的初始激活、其向 ER-质膜连接处的易位以及与 Orai1 通道的偶联。细胞内钙升高后，SARAF 和 STIM1 ID 之间的合作控制 CRAC 通道的慢钙依赖性失活。我们进一步表明，在 T 淋巴细胞中，SARAF 是 T 细胞受体诱发转录所必需的。综合所有这些数据，我们揭示了 SARAF 在 CRAC 通道的激活和失活过程中的双重调节作用，并表明 SARAF 可调节细胞内钙反应和下游基因表达。
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