Disease-associated keratin mutations reduce traction forces and compromise adhesion and collective migration
Disease-associated keratin mutations reduce traction forces and compromise adhesion and collective migration
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DOI：
10.1242/jcs.243956
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发表时间：
2020-07-01
影响因子：
4
通讯作者：
Magin, Thomas M.
中科院分区：
文献类型：
--
作者：
Fujiwara, Sachiko;Deguchi, Shinji;Magin, Thomas M.
角蛋白 (K) 中间丝蛋白构成上皮细胞中的主要细胞骨架成分。 K5 或 K14 的错义突变在基底表皮中高表达，可导致严重的皮肤起泡疾病单纯性大疱性表皮松解症 (EBS)。 EBS 相关突变会破坏角蛋白网络并改变角质形成细胞力学，然而，突变形成 EBS 病理学的分子机制仍不完全清楚。在这里，我们证明，与角蛋白缺陷的角质形成细胞相比，表达 K14(R125C) 的细胞会导致严重的 EBS，产生较低的牵引力，并伴有细胞分布改变的不成熟粘着斑。此外，突变的角质形成细胞在集体迁移过程中表现出方向性降低。值得注意的是，RhoA 活性在人 EBS 角质形成细胞中下调，Rho 激活可挽救 EBS 角质形成细胞的硬度依赖性细胞外基质 (ECM) 粘附形成。总的来说，我们的结果强烈表明，完整的角蛋白 IF 网络通过细胞-ECM 粘附形成和有组织的细胞迁移上游的 Rho 信号通路调节力转导。我们的研究结果提供了对 EBS 潜在病理生理学的见解。本文有对该论文第一作者的相关第一人称采访。
Keratin (K) intermediate filament proteins constitute the major cytoskeletal components in epithelial cells. Missense mutations in K5 or K14, highly expressed in the basal epidermis, cause the severe skin blistering disease epidermolysis bullosa simplex (EBS). EBS-associated mutations disrupt keratin networks and change keratinocyte mechanics, however, molecular mechanisms by which mutations shape EBS pathology remain incompletely understood. Here, we demonstrate that in contrast to keratin-deficient keratinocytes, cells expressing K14(R125C), causing severe EBS, generate lower traction forces, accompanied by immature focal adhesions with an altered cellular distribution. Furthermore, mutant keratinocytes displayed reduced directionality during collective migration. Notably, RhoA activity was downregulated in human EBS keratinocytes, and Rho activation rescued stiffness-dependent cell-extra cellular matrix (ECM) adhesion formation of EBS keratinocytes. Collectively, our results strongly suggest that intact keratin IF networks regulate mechanotransduction through a Rho signaling pathway upstream of cell-ECM adhesion formation and organized cell migration. Our findings provide insights into the underlying pathophysiology of EBS.This article has an associated First Person interview with the first author of the paper.