ARHGAP12 suppresses F-actin assembly to control epithelial tight junction mechanics and paracellular leak pathway permeability.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-04-22 Epub Date: 2025-04-07 DOI:10.1016/j.celrep.2025.115511

Hana Maldivita Tambrin, Yun Liu, Kexin Zhu, Xiang Teng, Yusuke Toyama, Yansong Miao, Alexander Ludwig

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引用次数: 0

Abstract

Tight junctions (TJs) control the paracellular transport of ions, solutes, and macromolecules across epithelial barriers. There is evidence that claudin-based ion transport (the pore pathway) and the paracellular transport of macromolecules (the leak pathway) are controlled independently. However, how leak pathway flux is regulated is unclear. Here, we have identified the Cdc42/Rac GTPase-activating protein ARHGAP12 as a specific activator of the leak pathway. ARHGAP12 is recruited to TJs via an interaction between its Src homology (SH3) domain and the TJ protein ZO-2 to suppress N-WASP-mediated F-actin assembly. This dampens junctional tension and promotes the paracellular transport of macromolecules without affecting ion flux. Mechanistically, we demonstrate that the ARHGAP12 tandem WW domain interacts directly with PPxR motifs in the proline-rich domain of N-WASP and thereby attenuates SH3-domain-mediated N-WASP oligomerization and Arp2/3-driven F-actin assembly. Collectively, our data indicate that branched F-actin networks regulate junctional tension to fine-tune the TJ leak pathway.

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ARHGAP12抑制f -肌动蛋白组装以控制上皮紧密连接机制和细胞旁渗漏途径的通透性。

紧密连接（TJs）控制离子、溶质和大分子跨越上皮屏障的细胞旁运输。有证据表明，基于claudin的离子运输（孔隙途径）和大分子的细胞旁运输（泄漏途径）是独立控制的。然而，泄漏途径的通量是如何调节的尚不清楚。在这里，我们已经确定了Cdc42/Rac gtpase激活蛋白ARHGAP12作为泄漏途径的特异性激活因子。ARHGAP12通过其Src同源结构域（SH3）和TJ蛋白ZO-2之间的相互作用被招募到TJ，抑制n - wasp介导的F-actin组装。这抑制了连接张力，促进了大分子的细胞旁运输，而不影响离子通量。在机制上，我们证明了ARHGAP12串联WW结构域直接与N-WASP富含脯氨酸结构域的PPxR基序相互作用，从而减弱了sh3结构域介导的N-WASP寡聚化和arp2 /3驱动的F-actin组装。总的来说，我们的数据表明，分支的f -肌动蛋白网络调节连接张力，微调TJ泄漏途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.