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MICAL2PV 抑制隧道纳米管的形成并调节线粒体运输。

MICAL2PV suppresses the formation of tunneling nanotubes and modulates mitochondrial trafficking.

机构信息

State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

University of Chinese Academy of Sciences, Beijing, China.

出版信息

EMBO Rep. 2021 Jul 5;22(7):e52006. doi: 10.15252/embr.202052006. Epub 2021 Jun 6.

DOI:10.15252/embr.202052006
PMID:34096155
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8366454/
Abstract

Tunneling nanotubes (TNTs) are actin-rich structures that connect two or more cells and mediate cargo exchange between spatially separated cells. TNTs transport signaling molecules, vesicles, organelles, and even pathogens. However, the molecular mechanisms regulating TNT formation remain unclear and little is known about the endogenous mechanisms suppressing TNT formation in lung cancer cells. Here, we report that MICAL2PV, a splicing isoform of the neuronal guidance gene MICAL2, is a novel TNT regulator that suppresses TNT formation and modulates mitochondrial distribution. MICAL2PV interacts with mitochondrial Rho GTPase Miro2 and regulates subcellular mitochondrial trafficking. Moreover, down-regulation of MICAL2PV enhances survival of cells treated with chemotherapeutical drugs. The monooxygenase (MO) domain of MICAL2PV is required for its activity to inhibit TNT formation by depolymerizing F-actin. Our data demonstrate a previously unrecognized function of MICAL2 in TNT formation and mitochondrial trafficking. Furthermore, our study uncovers a role of the MICAL2PV-Miro2 axis in mitochondrial trafficking, providing a mechanistic explanation for MICAL2PV activity in suppressing TNT formation and in modulating mitochondrial subcellular distribution.

摘要

隧道纳米管（TNTs）是富含肌动蛋白的结构，连接两个或更多的细胞，并介导空间分离的细胞之间的货物交换。TNTs 运输信号分子、囊泡、细胞器，甚至病原体。然而，调节 TNT 形成的分子机制尚不清楚，关于内源性抑制肺癌细胞 TNT 形成的机制知之甚少。在这里，我们报告说，神经元导向基因 MICAL2 的剪接异构体 MICAL2PV 是一种新型的 TNT 调节因子，它抑制 TNT 的形成并调节线粒体的分布。MICAL2PV 与线粒体 Rho GTPase Miro2 相互作用，并调节亚细胞线粒体的运输。此外，下调 MICAL2PV 可增强化疗药物处理的细胞的存活。MICAL2PV 的单加氧酶（MO）结构域对于其通过解聚 F-肌动蛋白抑制 TNT 形成的活性是必需的。我们的数据表明了 MICAL2 在 TNT 形成和线粒体运输中的以前未被认识的功能。此外，我们的研究揭示了 MICAL2PV-Miro2 轴在线粒体运输中的作用，为 MICAL2PV 抑制 TNT 形成和调节线粒体亚细胞分布的活性提供了机制解释。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5b6/8366454/fdedfaf7bd06/EMBR-22-e52006-g015.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5b6/8366454/517c70f9128c/EMBR-22-e52006-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5b6/8366454/ddffba54d2c0/EMBR-22-e52006-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5b6/8366454/f3321cbbc653/EMBR-22-e52006-g009.jpg
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