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微管-LUZP1 关联围绕紧密连接促进上皮细胞顶端缢缩。

A microtubule-LUZP1 association around tight junction promotes epithelial cell apical constriction.

机构信息

Laboratory of Biological Science, Graduate School of Medicine, Osaka University, Osaka, Japan.

Laboratory of Barriology and Cell Biology, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.

出版信息

EMBO J. 2021 Jan 15;40(2):e104712. doi: 10.15252/embj.2020104712. Epub 2020 Dec 21.

DOI:10.15252/embj.2020104712
PMID:33346378
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7809799/
Abstract

Apical constriction is critical for epithelial morphogenesis, including neural tube formation. Vertebrate apical constriction is induced by di-phosphorylated myosin light chain (ppMLC)-driven contraction of actomyosin-based circumferential rings (CRs), also known as perijunctional actomyosin rings, around apical junctional complexes (AJCs), mainly consisting of tight junctions (TJs) and adherens junctions (AJs). Here, we revealed a ppMLC-triggered system at TJ-associated CRs for vertebrate apical constriction involving microtubules, LUZP1, and myosin phosphatase. We first identified LUZP1 via unbiased screening of microtubule-associated proteins in the AJC-enriched fraction. In cultured epithelial cells, LUZP1 was found localized at TJ-, but not at AJ-, associated CRs, and LUZP1 knockout resulted in apical constriction defects with a significant reduction in ppMLC levels within CRs. A series of assays revealed that ppMLC promotes the recruitment of LUZP1 to TJ-associated CRs, where LUZP1 spatiotemporally inhibits myosin phosphatase in a microtubule-facilitated manner. Our results uncovered a hitherto unknown microtubule-LUZP1 association at TJ-associated CRs that inhibits myosin phosphatase, contributing significantly to the understanding of vertebrate apical constriction.

摘要

顶端缢缩对于上皮形态发生至关重要，包括神经管的形成。脊椎动物的顶端缢缩是由二磷酸化肌球蛋白轻链（ppMLC）驱动的、围绕着顶端连接复合体（AJC）的、以肌动球蛋白为基础的环形结构（CRs）的收缩引起的，这些 CRs 也被称为连接肌动球蛋白环。AJC 主要由紧密连接（TJ）和黏着连接（AJ）组成。在这里，我们揭示了一个涉及微管、LUZP1 和肌球蛋白磷酸酶的 ppMLC 触发的 TJ 相关 CRs 系统，用于脊椎动物的顶端缢缩。我们首先通过在 AJC 富集部分中进行无偏筛选鉴定了 LUZP1。在培养的上皮细胞中，LUZP1 定位于 TJ 相关的 CRs，但不在 AJ 相关的 CRs 上，并且 LUZP1 的敲除导致顶端缢缩缺陷，CRs 内的 ppMLC 水平显著降低。一系列实验表明，ppMLC 促进了 LUZP1 到 TJ 相关 CRs 的募集，在那里 LUZP1 以微管促进的方式在空间和时间上抑制肌球蛋白磷酸酶。我们的结果揭示了 TJ 相关 CRs 中以前未知的微管-LUZP1 关联，该关联抑制了肌球蛋白磷酸酶，这对理解脊椎动物的顶端缢缩有重要贡献。

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