Remodeling of ER-plasma membrane contact sites but not STIM1 phosphorylation inhibits Ca2+ influx in mitosis
Remodeling of ER-plasma membrane contact sites but not STIM1 phosphorylation inhibits Ca2+ influx in mitosis
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DOI：
10.1073/pnas.1821399116
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发表时间：
2019-05-21
影响因子：
11.1
通讯作者：
Machaca, Khaled
中科院分区：
文献类型：
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作者：
Yu, Fang;Hubrack, Satanay Z.;Machaca, Khaled
由内质网（ER）钙传感器基质相互作用分子1（STIM 1）和质膜（PM）通道Orai 1介导的钙库操纵的钙内流（SOCE）在有丝分裂期间受到抑制。STIM 1磷酸化被认为介导了这种抑制，但目前还不清楚是否涉及其他途径。在这里，我们证明使用各种方法，包括nonphosphorylatable STIM 1基因敲入小鼠，STIM 1磷酸化是不需要的SOCE抑制有丝分裂。相反，多个途径会聚以抑制有丝分裂中的Ca 2+内流。STIM 1与辅伴侣BAG 3相互作用并定位于有丝分裂中的自噬体，并且STIM 1蛋白水平降低。ER-PM接触位点（CS）的密度在有丝分裂中也显著降低，从而物理上阻止STIM 1和Orai 1相互作用以激活SOCE。我们的研究结果提供了深入了解ER-PM CS重塑有丝分裂过程中和细胞周期进程所需的Ca 2+内流的抑制机制的解释。
Store-operated Ca2+ entry (SOCE), mediated by the endoplasmic reticulum (ER) Ca2+ sensor stromal interaction molecule 1 (STIM1) and the plasma membrane (PM) channel Orai1, is inhibited during mitosis. STIM1 phosphorylation has been suggested to mediate this inhibition, but it is unclear whether additional pathways are involved. Here, we demonstrate using various approaches, including a nonphosphorylatable STIM1 knock-in mouse, that STIM1 phosphorylation is not required for SOCE inhibition in mitosis. Rather, multiple pathways converge to inhibit Ca2+ influx in mitosis. STIM1 interacts with the cochaperone BAG3 and localizes to autophagosomes in mitosis, and STIM1 protein levels are reduced. The density of ER-PM contact sites (CSs) is also dramatically reduced in mitosis, thus physically preventing STIM1 and Orai1 from interacting to activate SOCE. Our findings provide insights into ER-PM CS remodeling during mitosis and a mechanistic explanation of the inhibition of Ca2+ influx that is required for cell cycle progression.