Plakoglobin but not desmoplakin regulates keratinocyte cohesion via modulation of p38MAPK signaling.
Plakoglobin but not desmoplakin regulates keratinocyte cohesion via modulation of p38MAPK signaling.
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DOI：
10.1038/jid.2014.21
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发表时间：
2014-06
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影响因子：
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通讯作者：
V. Spindler;C. Dehner;S. Hübner;J. Waschke
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作者：
V. Spindler;C. Dehner;S. Hübner;J. Waschke
斑珠蛋白（Plakoglobin，Pg）和桥粒斑蛋白（desmoplakin，DP）是桥粒内的衔接蛋白，在桥粒钙粘蛋白作为跨膜粘附分子和中间丝细胞骨架之间提供机械连接。在严重的皮肤起泡性疾病天疱疮，自身抗体对桥粒粘附分子诱导角质形成细胞凝聚力的损失至少部分通过p38丝裂原活化蛋白激酶（p38 MAPK）的激活和耗尽的桥粒成分，我们评估的Pg和DP的作用，在p38 MAPK依赖的细胞粘附的损失。在解离试验中，Pg或DP的沉默降低了培养的人角质形成细胞的凝聚力。然而，Pg而不是DP沉默引起p38 MAPK依赖的角蛋白丝塌陷和细胞解离的激活。有趣的是，胞核Pg而不是胞核Pg挽救了细胞粘附和角蛋白收缩的丧失。与此一致，Pg调节桥粒粘附分子桥粒芯糖蛋白3和连接到桥粒复合物的p38 MAPK的水平。我们的数据表明，在控制细胞粘附的角蛋白丝组织通过p38 MAPK依赖性调节细胞核Pg的作用。
Plakoglobin (Pg) and desmoplakin (DP) are adapter proteins within the desmosome, providing a mechanical link between desmosomal cadherins as transmembrane adhesion molecules and the intermediate filament cytoskeleton. As in the severe skin blistering disease pemphigus, autoantibodies against desmosomal adhesion molecules induce loss of keratinocyte cohesion at least in part via p38 mitogen-activated protein kinase (p38MAPK) activation and depletion of desmosomal components, we evaluated the roles of Pg and DP in the p38MAPK-dependent loss of cell adhesion. Silencing of either Pg or DP reduced cohesion of cultured human keratinocytes in dissociation assays. However, Pg but not DP silencing caused activation of p38MAPK-dependent keratin filament collapse and cell dissociation. Interestingly, extranuclear but not nuclear Pg rescued loss of cell adhesion and keratin retraction. In line with this, Pg regulated the levels of the desmosomal adhesion molecule desmoglein 3 and tethered p38MAPK to desmosomal complexes. Our data demonstrate a role of extranuclear Pg in controlling cell adhesion via p38MAPK-dependent regulation of keratin filament organization.