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在有丝分裂中，内质网-质膜接触位点的重构但不是 STIM1 磷酸化会抑制 Ca2+内流。

Remodeling of ER-plasma membrane contact sites but not STIM1 phosphorylation inhibits Ca influx in mitosis.

机构信息

Department of Physiology and Biophysics, Weill Cornell Medicine Qatar, Doha, Qatar, 24144.

Calcium Signaling Group, Weill Cornell Medicine Qatar, Doha, Qatar, 24144.

出版信息

Proc Natl Acad Sci U S A. 2019 May 21;116(21):10392-10401. doi: 10.1073/pnas.1821399116. Epub 2019 May 7.

DOI:10.1073/pnas.1821399116
PMID:31064875
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6535005/
Abstract

Store-operated Ca entry (SOCE), mediated by the endoplasmic reticulum (ER) Ca 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 Ca 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 Ca influx that is required for cell cycle progression.

摘要

由内质网 (ER) Ca 传感器基质相互作用分子 1 (STIM1) 和质膜 (PM) 通道 Orai1 介导的储存操作型 Ca 内流 (SOCE) 在有丝分裂期间受到抑制。STIM1 磷酸化被认为介导了这种抑制，但尚不清楚是否涉及其他途径。在这里，我们使用各种方法证明，包括一种不可磷酸化的 STIM1 敲入小鼠，STIM1 磷酸化不是有丝分裂中 SOCE 抑制所必需的。相反，多种途径汇聚在一起抑制有丝分裂中的 Ca 内流。在有丝分裂过程中，STIM1 与共伴侣 BAG3 相互作用，并定位于自噬体中，并且 STIM1 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，从而从物理上阻止 STIM1 和 Orai1 相互作用以激活 SOCE。我们的研究结果为有丝分裂期间 ER-PM CS 重塑提供了深入了解，并为细胞周期进程所需的 Ca 内流抑制提供了一种机制解释。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/588c/6535005/d4f6b3549fe4/pnas.1821399116fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/588c/6535005/d6bb8dbba3c5/pnas.1821399116fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/588c/6535005/56821f919c42/pnas.1821399116fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/588c/6535005/70d5299d576a/pnas.1821399116fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/588c/6535005/b503aea8879d/pnas.1821399116fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/588c/6535005/d4f6b3549fe4/pnas.1821399116fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/588c/6535005/d6bb8dbba3c5/pnas.1821399116fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/588c/6535005/56821f919c42/pnas.1821399116fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/588c/6535005/70d5299d576a/pnas.1821399116fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/588c/6535005/b503aea8879d/pnas.1821399116fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/588c/6535005/d4f6b3549fe4/pnas.1821399116fig05.jpg

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