Phosphorylation of alpha-CateninS641 Suppresses the NF-kappaB Pathway in Fibroblasts to Activate Skin Wound Repair.
Phosphorylation of alpha-CateninS641 Suppresses the NF-kappaB Pathway in Fibroblasts to Activate Skin Wound Repair.
复制标题
α-CateninS641 的磷酸化抑制成纤维细胞中的 NF-kappaB 通路，从而激活皮肤伤口修复。
DOI：
10.1016/j.jid.2021.09.037
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发表时间：
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影响因子：
6.5
通讯作者：
Jin Litai
中科院分区：
文献类型：
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作者：
Shen Yingjie;Zhu Zhongxin;Cong Weitao;Jiang Mengying;Wang Jianan;Chen Xixi;Wang Nan;Yu Ying;Dong Yetong;Liu Zhili;Sun Jia;Gong Wenjie;Zhang Siyi;Kim Kwonseop;Jin Litai
皮肤创伤愈合是一个复杂的过程，涉及复杂的分子机制，目前尚不清楚。创伤后动态平衡的恢复需要成纤维细胞的重塑功能。在这项研究中，我们发现在创伤过程中，成纤维细胞中α-Catenin S641的磷酸化水平上调，从而加速了成纤维细胞的增殖和迁移，从而恢复了皮肤屏障。在伤口边缘，磷酸化的α-Catenin S641稳定了IκBα，从而削弱了NF-κB靶基因的表达，促进了成纤维细胞的增殖和迁移。机械地，磷酸化的α-连环蛋白S641阻断了K48连接的多泛素化和IκBα的蛋白酶体降解。此外，我们还发现在S641中，表皮生长因子/表皮生长因子受体/细胞角蛋白2α通过磷酸化α-连环蛋白，作为α-连环蛋白的关键上游信号通路发挥作用。创伤修复在小鼠皮肤中被显著破坏，其中成纤维细胞中的α-连环蛋白磷酸化和CK2CK2α激酶活性被干扰。这些发现为创伤后成纤维细胞增殖和迁移的分子控制提供了洞察力，并确定了治疗创伤修复的潜在靶点。
Skin wound healing is a complex process involving intricate molecular mechanisms that remain unknown. Restoration of homeostasis after wounding requires the remodeling function of fibroblasts. In this study, we show that phosphorylation of α-cateninS641was upregulated in fibroblasts during wounding, which accelerated their proliferation and migration to restore the skin barrier. At the wound edge, phosphorylated α-cateninS641stabilized IκBα and thereby impaired the expression of NF-κB target genes to promote proliferation and migration of fibroblasts. Mechanically, phosphorylated α-cateninS641blocked K48-linked polyubiquitination and proteasomal degradation of IκBα. Moreover, we also showed that EGF/EGFR/CK2α functioned as key upstream signaling of α-catenin by phosphorylating α-catenin at S641. Wound repair was significantly disrupted in the skin of mice in which α-catenin phosphorylation and CK2α kinase activity were perturbed in fibroblasts. These findings provide insights into the molecular control of fibroblast proliferation and migration in response to wounding and identify potential targets for the treatment of defective wound repair.