Age-Onset Phosphorylation of a Minor Actin Variant Promotes Intestinal Barrier Dysfunction
Age-Onset Phosphorylation of a Minor Actin Variant Promotes Intestinal Barrier Dysfunction
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DOI：
10.1016/j.devcel.2019.11.001
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发表时间：
2019-12-02
影响因子：
11.8
通讯作者：
Douglas, Peter M.
中科院分区：
文献类型：
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作者：
Egge, Nathan;Arneaud, Sonja L. B.;Douglas, Peter M.
与年龄相关的细胞间相互作用的衰退损害了细胞在组织内紧密结合并形成功能屏障的能力。这种屏障功能障碍损害器官生理，导致全身衰竭。肌动蛋白细胞骨架是维持组织结构的关键决定因素。然而，目前还不清楚年龄是如何破坏肌动蛋白细胞骨架的，以及这反过来又是如何提高死亡率的。在这里，我们发现了一种低丰度的肌动蛋白变体ACT-5的非特征磷酸化，破坏了秀丽隐杆线虫肠道屏障的完整性并加速了发病机制。年龄相关的热休克转录因子HSF-1的缺失会破坏JUN激酶和蛋白磷酸酶I的平衡，从而增加肌钙蛋白结合位点的ACT-5磷酸化。磷酸化的ACT-5加速肠亚根尖末端网的腐烂，并损害其与细胞连接的相互作用。这损害了屏障的完整性，促进了发病机制，并导致了死亡率。因此，我们提供了与年龄相关的特化肌动蛋白网络损失影响组织完整性的分子机制。
Age-associated decay of intercellular interactions impairs the cells' capacity to tightly associate within tissues and form a functional barrier. This barrier dysfunction compromises organ physiology and contributes to systemic failure. The actin cytoskeleton represents a key determinant in maintaining tissue architecture. Yet, it is unclear how age disrupts the actin cytoskeleton and how this, in turn, promotes mortality. Here, we show that an unchar-acterized phosphorylation of a low-abundant actin variant, ACT-5, compromises integrity of the C. elegans intestinal barrier and accelerates pathogenesis. Age-related loss of the heat-shock transcription factor, HSF-1, disrupts the JUN kinase and protein phosphatase I equilibrium which increases ACT-5 phosphorylation within its troponin binding site. Phosphorylated ACT-5 accelerates decay of the intestinal subapical terminal web and impairs its interactions with cell junctions. This compromises barrier integrity, promotes pathogenesis, and drives mortality. Thus, we provide the molecular mechanism by which age-associated loss of specialized actin networks impacts tissue integrity.