Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK.
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.
Mol Cell. 2021 Dec 2;81(23):4784-4798.e7. doi: 10.1016/j.molcel.2021.10.025. Epub 2021 Nov 19.
Calcium influx through plasma membrane calcium release-activated calcium (CRAC) channels, which are formed of hexamers of Orai1, is a potent trigger for many important biological processes, most notably in T cell-mediated immunity. Through a bioinformatics-led cell biological screen, we have identified Orai1 as a substrate for the rhomboid intramembrane protease RHBDL2. We show that RHBDL2 prevents stochastic calcium signaling in unstimulated cells through conformational surveillance and cleavage of inappropriately activated Orai1. A conserved disease-linked proline residue is responsible for RHBDL2's recognizing the active conformation of Orai1, which is required to sharpen switch-like signaling triggered by store-operated calcium entry. Loss of RHBDL2 control of CRAC channel activity causes severe dysregulation of downstream CRAC channel effectors, including transcription factor activation, inflammatory cytokine expression, and T cell activation. We propose that this surveillance function may represent an ancient activity of rhomboid proteases in degrading unwanted signaling proteins.
通过质膜钙释放激活钙（CRAC）通道的钙离子内流，这是由 Orai1 的六聚体形成的，是许多重要生物过程的有力触发因素，尤其是在 T 细胞介导的免疫中。通过生物信息学指导的细胞生物学筛选，我们已经确定 Orai1 是菱形跨膜蛋白酶 RHBDL2 的底物。我们表明，RHBDL2 通过构象监测和切割不当激活的 Orai1，防止未受刺激的细胞中的随机钙信号。一个保守的疾病相关脯氨酸残基负责 RHBDL2 识别 Orai1 的活性构象，这是触发由储存操作钙进入引发的类似开关的信号所必需的。CRAC 通道活性的 RHBDL2 控制丧失导致下游 CRAC 通道效应物的严重失调，包括转录因子激活、炎性细胞因子表达和 T 细胞激活。我们提出，这种监测功能可能代表菱形蛋白酶在降解不需要的信号蛋白中的古老活性。
