STIM1 functions as a proton sensor to coordinate cytosolic pH with store-operated calcium entry.

IF 4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yilan Chen, Panpan Liu, Ziyi Zhong, Hanhan Zhang, Aomin Sun, Youjun Wang
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引用次数: 0

Abstract

The meticulous regulation of intracellular pH (pHi) is crucial for maintaining cellular function and homeostasis, impacting physiological processes such as heart rhythm, cell migration, proliferation, and differentiation. Dysregulation of pHi is implicated in various pathologies such as arrhythmias, cancer, and neurodegenerative diseases. Here, we explore the role of STIM1, an ER calcium (Ca2+) sensor mediating Store Operated Ca2+ Entry (SOCE), in sensing pHi changes. Our study reveals that STIM1 functions as a sensor for pHi changes, independent of its Ca2+-binding state. Through comprehensive experimental approaches including confocal microscopy, FRET-based sensors, and mutagenesis, we demonstrate that changes in pHi induce conformational alterations in STIM1, thereby modifying its subcellular localization and activity. We identify two conserved histidine within STIM1 essential for sensing pHi shifts. Moreover, intracellular alkalization induced by agents such as Angiotensin II or NH4Cl enhances STIM1-mediated SOCE, promoting cardiac hypertrophy. These findings reveal a novel facet of STIM1 as a multi-modal stress sensor that coordinates cellular responses to both Ca2+ and pH fluctuations. This dual functionality underscores its potential as a therapeutic target for diseases associated with pH and Ca2+ dysregulation.

STIM1 发挥质子传感器的作用,协调细胞膜 pH 值与钙储存操作的钙输入。
细胞内 pH 值(pHi)的精细调节对维持细胞功能和平衡至关重要,影响着心律、细胞迁移、增殖和分化等生理过程。pHi 失调与心律失常、癌症和神经退行性疾病等多种病症有关。在这里,我们探讨了 STIM1 在感知 pHi 变化中的作用,STIM1 是一种 ER 钙(Ca2+)传感器,介导存储操作 Ca2+ 进入(SOCE)。我们的研究揭示了 STIM1 作为 pHi 变化传感器的功能,与其 Ca2+ 结合状态无关。通过共聚焦显微镜、基于 FRET 的传感器和诱变等综合实验方法,我们证明了 pHi 的变化会诱导 STIM1 的构象变化,从而改变其亚细胞定位和活性。我们在 STIM1 中发现了两个保守组氨酸,它们对感知 pHi 的变化至关重要。此外,血管紧张素 II 或 NH4Cl 等物质诱导的细胞内碱化会增强 STIM1 介导的 SOCE,从而促进心脏肥大。这些发现揭示了 STIM1 作为多模式应激传感器的新面貌,它能协调细胞对 Ca2+ 和 pH 波动的反应。这种双重功能突显了它作为与 pH 和 Ca2+ 失调相关疾病的治疗靶点的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Biological Chemistry
Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry
自引率
4.20%
发文量
1233
期刊介绍: The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.
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