Occludin S408 phosphorylation regulates tight junction protein interactions and barrier function.
Occludin S408 phosphorylation regulates tight junction protein interactions and barrier function.
复制标题
occludin S408磷酸化调节紧密的连接蛋白相互作用和屏障功能。
DOI：
10.1083/jcb.201010065
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发表时间：
2011-05-02
期刊：
影响因子：
--
通讯作者：
Turner JR
中科院分区：
文献类型：
--
作者：
Raleigh DR;Boe DM;Yu D;Weber CR;Marchiando AM;Bradford EM;Wang Y;Wu L;Schneeberger EE;Shen L;Turner JR
Occludin S408磷酸化调节occludin、ZO-1和选择Claudins之间的相互作用，以确定紧密连接的分子结构和屏障功能。尽管紧密连接蛋白occludin的C末端细胞质尾巴被严重磷酸化，但大多数单个位点的功能影响尚不清楚。在这里，我们表明，抑制CK2介导的阻滞素S408磷酸化通过减少细胞旁阳离子流量来提高跨上皮细胞阻力。这一规定需要occludin、claudin-1、claudin-2和ZO-1。S408去磷酸化减少了闭塞蛋白交换，但增加了ZO-1、claudin-1和claudin-2的交换，从而导致这些蛋白的可移动部分聚合。Claudin-4交换不受影响。介导与occludin和claudins相互作用的ZO-1结构域是增加claudin-2交换所必需的，这表明组装了一种磷酸化敏感的蛋白质复合体。与此一致的是，与S408D相比，Claudin-1和Claudin-2，而不是Claudin-4，与S408A occludin Tail的结合增加。最后，抑制CK2可逆转IL-13诱导的Claudin-2依赖的屏障丧失。因此，occludin S408去磷酸化通过重塑紧密连接蛋白的动态行为以及occludin、ZO-1和SELECT Claudins之间的分子间相互作用来调节细胞旁通透性，并可能在炎症相关屏障功能障碍中具有治疗潜力。
Occludin S408 phosphorylation regulates interactions between occludin, ZO-1, and select claudins to define tight junction molecular structure and barrier function. Although the C-terminal cytoplasmic tail of the tight junction protein occludin is heavily phosphorylated, the functional impact of most individual sites is undefined. Here, we show that inhibition of CK2-mediated occludin S408 phosphorylation elevates transepithelial resistance by reducing paracellular cation flux. This regulation requires occludin, claudin-1, claudin-2, and ZO-1. S408 dephosphorylation reduces occludin exchange, but increases exchange of ZO-1, claudin-1, and claudin-2, thereby causing the mobile fractions of these proteins to converge. Claudin-4 exchange is not affected. ZO-1 domains that mediate interactions with occludin and claudins are required for increases in claudin-2 exchange, suggesting assembly of a phosphorylation-sensitive protein complex. Consistent with this, binding of claudin-1 and claudin-2, but not claudin-4, to S408A occludin tail is increased relative to S408D. Finally, CK2 inhibition reversed IL-13–induced, claudin-2–dependent barrier loss. Thus, occludin S408 dephosphorylation regulates paracellular permeability by remodeling tight junction protein dynamic behavior and intermolecular interactions between occludin, ZO-1, and select claudins, and may have therapeutic potential in inflammation-associated barrier dysfunction.
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影响因子：
7.8
作者：
Furuse, Mikio;Hata, Masaki;Furuse, Kyoko;Yoshida, Yoko;Haratake, Akinori;Sugitani, Yoshinobu;Noda, Tetsuo;Kubo, Akiharu;Tsukita, Shoichiro
通讯作者：
Tsukita, Shoichiro
影响因子：
5.5
作者：
Colegio, OR;Van Itallie, C;Anderson, JM
通讯作者：
Anderson, JM
影响因子：
2.4
作者：
CLAUDE, P
通讯作者：
CLAUDE, P
影响因子：
8
作者：
Blasig, IE;Winkler, L;Piontek, J
通讯作者：
Piontek, J
通过表达突变型紧密连接膜蛋白，细胞旁通透性和跨上皮电阻的功能性分离以及顶端-基底外侧膜内扩散屏障的破坏。
影响因子：
7.8
作者：
Balda, M S;Whitney, J A;Flores, C;Gonzalez, S;Cereijido, M;Matter, K
通讯作者：
Matter, K