A Weak Link with Actin Organizes Tight Junctions to Control Epithelial Permeability.
A Weak Link with Actin Organizes Tight Junctions to Control Epithelial Permeability.
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DOI：
10.1016/j.devcel.2020.07.022
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发表时间：
2020-09-28
影响因子：
11.8
通讯作者：
Fletcher DA
中科院分区：
文献类型：
--
作者：
Belardi B;Hamkins-Indik T;Harris AR;Kim J;Xu K;Fletcher DA
在脊椎动物中，上皮细胞的通透性是由紧密连接（TJ）的专门的粘附膜蛋白，衔接蛋白，和肌动蛋白细胞骨架形成的。尽管TJ的关键生理作用，TJ组装如何设置上皮组织的渗透性的分子水平的理解是缺乏的。在这里，我们确定了一个28个氨基酸序列的TJ衔接蛋白ZO-1，负责肌动蛋白结合，并表明这种相互作用是必不可少的TJ渗透性。在adherens交界处的强相互作用相反，我们发现，ZO-1和肌动蛋白之间的亲和力是令人惊讶的弱，我们提出了一个模型的基础上动力学捕获来解释如何亲和力可能会影响TJ组装。最后，通过调节ZO-1对肌动蛋白的亲和力，我们证明了上皮细胞单层可以被设计成具有一系列的渗透性，这为治疗转运障碍和改善药物递送指明了一个有希望的靶点。紧密连接负责设置上皮组织的渗透性。Belardi，Hamkins-Indik等人发现紧密连接的ZO-1和肌动蛋白之间的弱缔合对于产生稳健的屏障功能是必要的。通过改变ZO-1的肌动蛋白结合行为，上皮组织可以被改造成具有一系列渗透性。
In vertebrates, epithelial permeability is regulated by the tight junction (TJ) formed by specialized adhesive membrane proteins, adaptor proteins, and the actin cytoskeleton. Despite the TJ’s critical physiological role, a molecular-level understanding of how TJ assembly sets the permeability of epithelial tissue is lacking. Here, we identify a 28-amino acid sequence in the TJ adaptor protein ZO-1 that is responsible for actin binding and show that this interaction is essential for TJ permeability. In contrast to the strong interactions at the adherens junction, we find that the affinity between ZO-1 and actin is surprisingly weak, and we propose a model based on kinetic trapping to explain how affinity could affect TJ assembly. Finally, by tuning the affinity of ZO-1 to actin, we demonstrate that epithelial monolayers can be engineered with a spectrum of permeabilities, which points to a promising target for treating transport disorders and improving drug delivery. Tight Junctions are responsible for setting the permeability of epithelial tissue. Belardi, Hamkins-Indik et al. find that a weak association between ZO-1 of the Tight Junction and actin is necessary for generating robust barrier function. By modifying ZO-1’s actin-binding behavior, epithelial tissue can be engineered with a spectrum of permeabilities.
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影响因子：
64.5
作者：
Drees, F;Pokutta, S;Weis, WI
通讯作者：
Weis, WI
三个紧密连接相关的Maguks ZO-1，ZO-2和ZO-3与Claudins的Cooh Termini直接结合。
DOI：
10.1083/jcb.147.6.1351
发表时间：
1999-12-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Itoh M;Furuse M;Morita K;Kubota K;Saitou M;Tsukita S
通讯作者：
Tsukita S
影响因子：
82.9
作者：
Graham, W. Vallen;He, Weiqi;Turner, Jerrold R.
通讯作者：
Turner, Jerrold R.
DOI：
10.1126/science.1254211
发表时间：
2014-10-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Buckley CD;Tan J;Anderson KL;Hanein D;Volkmann N;Weis WI;Nelson WJ;Dunn AR
通讯作者：
Dunn AR
影响因子：
16.6
作者：
de Beco S;Vaidžiulytė K;Manzi J;Dalier F;di Federico F;Cornilleau G;Dahan M;Coppey M
通讯作者：
Coppey M