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TMEM25 是一个 Par3 结合蛋白，可在紧密连接发育过程中减弱 Claudin 的组装。

TMEM25 is a Par3-binding protein that attenuates claudin assembly during tight junction development.

机构信息

Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

出版信息

EMBO Rep. 2024 Jan;25(1):144-167. doi: 10.1038/s44319-023-00018-0. Epub 2023 Dec 18.

DOI:10.1038/s44319-023-00018-0
PMID:38177906
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10897455/
Abstract

The tight junction (TJ) in epithelial cells is formed by integral membrane proteins and cytoplasmic scaffolding proteins. The former contains the claudin family proteins with four transmembrane segments, while the latter includes Par3, a PDZ domain-containing adaptor that organizes TJ formation. Here we show the single membrane-spanning protein TMEM25 localizes to TJs in epithelial cells and binds to Par3 via a PDZ-mediated interaction with its C-terminal cytoplasmic tail. TJ development during epithelial cell polarization is accelerated by depletion of TMEM25, and delayed by overexpression of TMEM25 but not by that of a C-terminally deleted protein, indicating a regulatory role of TMEM25. TMEM25 associates via its N-terminal extracellular domain with claudin-1 and claudin-2 to suppress their cis- and trans-oligomerizations, both of which participate in TJ strand formation. Furthermore, Par3 attenuates TMEM25-claudin association via binding to TMEM25, implying its ability to affect claudin oligomerization. Thus, the TJ protein TMEM25 appears to negatively regulate claudin assembly in TJ formation, which regulation is modulated by its interaction with Par3.

摘要

紧密连接（TJ）在上皮细胞中由整合膜蛋白和细胞质支架蛋白形成。前者包含具有四个跨膜片段的 Claudin 家族蛋白，而后者包括 Par3，它是一种 PDZ 结构域包含的衔接蛋白，可组织 TJ 的形成。在这里，我们展示了单一跨膜蛋白 TMEM25 在上皮细胞中定位于 TJ，并通过 PDZ 介导的与其 C 末端细胞质尾巴的相互作用与 Par3 结合。上皮细胞极化过程中 TJ 的发育通过 TMEM25 的耗竭而加速，通过 TMEM25 的过表达而延迟，但通过 C 末端缺失的蛋白的过表达则不会延迟，表明 TMEM25 具有调节作用。TMEM25 通过其 N 末端细胞外结构域与 Claudin-1 和 Claudin-2 结合，以抑制它们的顺式和反式寡聚化，这两者都参与 TJ 链的形成。此外，Par3 通过与 TMEM25 结合来减弱 TMEM25-Claudin 关联，暗示其影响 Claudin 寡聚化的能力。因此，TJ 蛋白 TMEM25 似乎负调控 TJ 形成中的 Claudin 组装，这种调节受其与 Par3 的相互作用调节。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/51851bcb85f0/44319_2023_18_Fig11_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/57228565c6a4/44319_2023_18_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/4b9e9822b087/44319_2023_18_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/27e9e80a83ef/44319_2023_18_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/7a18d9b828ce/44319_2023_18_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/12237e9e2ba6/44319_2023_18_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/51851bcb85f0/44319_2023_18_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/ba1b951e273c/44319_2023_18_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/9c154e6fc458/44319_2023_18_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/50e22e935ee3/44319_2023_18_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/f540557b663c/44319_2023_18_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/1f44f510e60d/44319_2023_18_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/57228565c6a4/44319_2023_18_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/4b9e9822b087/44319_2023_18_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/27e9e80a83ef/44319_2023_18_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/7a18d9b828ce/44319_2023_18_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/12237e9e2ba6/44319_2023_18_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d799/10897455/51851bcb85f0/44319_2023_18_Fig11_ESM.jpg

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