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肌球蛋白磷酸酶靶向亚基1控制含Rab7囊泡的定位和运动：肌球蛋白磷酸酶是一种胞质动力蛋白调节剂吗？

Myosin phosphatase targeting subunit1 controls localization and motility of Rab7-containing vesicles: Is myosin phosphatase a cytoplasmic dynein regulator?

作者信息

Matsumura Fumio, Murayama Takashi, Kuriyama Ryoko, Matsumura Aya, Yamashiro Shigeko

机构信息

Department of Molecular Biology & Biochemistry, Rutgers University, Piscataway, New Jersey, USA.

Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan.

出版信息

Cytoskeleton (Hoboken). 2024 Dec;81(12):872-882. doi: 10.1002/cm.21871. Epub 2024 May 3.

DOI:10.1002/cm.21871
PMID:38700016
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11615836/
Abstract

Myosin phosphatase targeting subunit1 (MYPT1) is a critical subunit of myosin phosphatase (MP), which brings PP1Cδ phosphatase and its substrate together. We previously showed that MYPT1 depletion resulted in oblique chromatid segregation. Therefore, we hypothesized that MYPT1 may control microtubule-dependent motor activity. Dynein, a minus-end microtubule motor, is known to be involved in mitotic spindle assembly. We thus examined whether MYPT1 and dynein may interact. Proximity ligation assay and co-immunoprecipitation revealed that MYPT1 and dynein intermediate chain (DIC) were associated. We found that DIC phosphorylation is increased in MYPT1-depleted cells in vivo, and that MP was able to dephosphorylate DIC in vitro. MYPT1 depletion also altered the localization and motility of Rab7-containing vesicles. MYPT1-depletion dispersed the perinuclear Rab7 localization to the peripheral in interphase cells. The dispersed Rab7 localization was rescued by microinjection of a constitutively active, truncated MYPT1 mutant, supporting that MP is responsible for the altered Rab7 localization. Analyses of Rab7 vesicle trafficking also revealed that minus-end transport was reduced in MYPT1-depleted cells. These results suggest an unexpected role of MP: MP controls dynein activity in both mitotic and interphase cells, possibly by dephosphorylating dynein subunits including DIC.

摘要

肌球蛋白磷酸酶靶向亚基1（MYPT1）是肌球蛋白磷酸酶（MP）的关键亚基，它将PP1Cδ磷酸酶与其底物结合在一起。我们之前表明，MYPT1缺失会导致染色单体倾斜分离。因此，我们推测MYPT1可能控制微管依赖性运动活性。动力蛋白是一种负端微管马达，已知其参与有丝分裂纺锤体组装。因此，我们研究了MYPT1和动力蛋白是否可能相互作用。邻近连接分析和免疫共沉淀显示，MYPT1和动力蛋白中间链（DIC）相关联。我们发现，在体内MYPT1缺失的细胞中DIC磷酸化增加，并且MP在体外能够使DIC去磷酸化。MYPT1缺失还改变了含Rab7囊泡的定位和运动。在间期细胞中，MYPT1缺失使核周Rab7定位分散到外周。通过显微注射组成型活性截短的MYPT1突变体可挽救分散的Rab7定位，这支持MP负责Rab7定位改变。对Rab7囊泡运输的分析还显示，在MYPT1缺失的细胞中负端运输减少。这些结果提示了MP一个意想不到的作用：MP在有丝分裂和间期细胞中控制动力蛋白活性，可能是通过使包括DIC在内的动力蛋白亚基去磷酸化来实现。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4b/11615836/5fb11a93766e/CM-81-872-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4b/11615836/979c1f263ce1/CM-81-872-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4b/11615836/bb9f79eea0ab/CM-81-872-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4b/11615836/bd28b723b10b/CM-81-872-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4b/11615836/264289d6f78c/CM-81-872-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4b/11615836/5fb11a93766e/CM-81-872-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4b/11615836/979c1f263ce1/CM-81-872-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4b/11615836/bb9f79eea0ab/CM-81-872-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4b/11615836/bd28b723b10b/CM-81-872-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4b/11615836/d4f7fba483a3/CM-81-872-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4b/11615836/264289d6f78c/CM-81-872-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4b/11615836/5fb11a93766e/CM-81-872-g006.jpg

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本文引用的文献

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J Biol Chem. 2023 Jun;299(6):104735. doi: 10.1016/j.jbc.2023.104735. Epub 2023 Apr 21.
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MYPT1, regulated by miR-19b-3p inhibits the progression of non-small cell lung cancer via inhibiting the activation of wnt/β-catenin signaling.肌球蛋白轻链磷酸酶 1（MYPT1）受 miR-19b-3p 调控，通过抑制 wnt/β-连环蛋白信号通路的激活抑制非小细胞肺癌的进展。
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新型环状 RNA circSOBP 通过调控 miR-141-3p/MYPT1/p-MLC2 轴影响前列腺癌细胞的阿米巴样运动。
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Cryo-EM shows how dynactin recruits two dyneins for faster movement.低温电子显微镜显示了动力蛋白激活因子如何招募两个动力蛋白以实现更快的运动。
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