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内质网维持质膜修复所需的离子稳态。

Endoplasmic reticulum maintains ion homeostasis required for plasma membrane repair.

作者信息

Chandra Goutam, Sreetama Sen Chandra, Mázala Davi A G, Charton Karine, VanderMeulen Jack H, Richard Isabelle, Jaiswal Jyoti K

机构信息

Center of Genetic Medicine Research, Children's National Health System, Washington, DC.

Généthon, Institut National de la Santé et de la Recherche Médicale, U951, INTEGRARE Research Unit, University Paris-Saclay, Evry, France.

出版信息

J Cell Biol. 2021 May 3;220(5). doi: 10.1083/jcb.202006035.

DOI:10.1083/jcb.202006035
PMID:33688936
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7953257/
Abstract

Of the many crucial functions of the ER, homeostasis of physiological calcium increase is critical for signaling. Plasma membrane (PM) injury causes a pathological calcium influx. Here, we show that the ER helps clear this surge in cytoplasmic calcium through an ER-resident calcium pump, SERCA, and a calcium-activated ion channel, Anoctamin 5 (ANO5). SERCA imports calcium into the ER, and ANO5 supports this by maintaining electroneutrality of the ER lumen through anion import. Preventing either of these transporter activities causes cytosolic calcium overload and disrupts PM repair (PMR). ANO5 deficit in limb girdle muscular dystrophy 2L (LGMD2L) patient cells compromises their cytosolic and ER calcium homeostasis. By generating a mouse model of LGMD2L, we find that PM injury causes cytosolic calcium overload and compromises the ability of ANO5-deficient myofibers to repair. Addressing calcium overload in ANO5-deficient myofibers enables them to repair, supporting the requirement of the ER in calcium homeostasis in injured cells and facilitating PMR.

摘要

在内质网（ER）的众多关键功能中，生理钙增加的稳态对于信号传导至关重要。质膜（PM）损伤会导致病理性钙内流。在此，我们表明内质网通过内质网驻留钙泵——肌浆网钙ATP酶（SERCA）和钙激活离子通道—— anoctamin 5（ANO5），帮助清除细胞质中钙的这种激增。SERCA将钙导入内质网，而ANO5通过导入阴离子来维持内质网腔的电中性，从而支持这一过程。阻止这两种转运蛋白的任何一种活性都会导致胞质钙超载并破坏质膜修复（PMR）。肢带型肌营养不良2L（LGMD2L）患者细胞中ANO5的缺乏损害了它们的胞质和内质网钙稳态。通过构建LGMD2L小鼠模型，我们发现质膜损伤会导致胞质钙超载，并损害ANO5缺陷型肌纤维的修复能力。解决ANO5缺陷型肌纤维中的钙超载问题能使它们进行修复，这支持了内质网在受损细胞钙稳态中的需求，并促进了质膜修复。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9f4/7953257/4b10f9b8fe20/JCB_202006035_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9f4/7953257/22a70611e6c3/JCB_202006035_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9f4/7953257/6f91add79527/JCB_202006035_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9f4/7953257/c47fe8a39499/JCB_202006035_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9f4/7953257/91ca3050a036/JCB_202006035_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9f4/7953257/1e06d803641c/JCB_202006035_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9f4/7953257/62cb25a823a8/JCB_202006035_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9f4/7953257/4b10f9b8fe20/JCB_202006035_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9f4/7953257/22a70611e6c3/JCB_202006035_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9f4/7953257/6f91add79527/JCB_202006035_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9f4/7953257/c47fe8a39499/JCB_202006035_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9f4/7953257/91ca3050a036/JCB_202006035_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9f4/7953257/1e06d803641c/JCB_202006035_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9f4/7953257/62cb25a823a8/JCB_202006035_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9f4/7953257/4b10f9b8fe20/JCB_202006035_Fig4.jpg

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TMEM16E/ANO5 mutations related to bone dysplasia or muscular dystrophy cause opposite effects on lipid scrambling.TMEM16E/ANO5 基因突变与骨发育不良或肌肉萎缩症有关，会对脂质翻转产生相反的影响。
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