Desmosome disassembly in response to pemphigus vulgaris IgG occurs in distinct phases and can be reversed by expression of exogenous Dsg3.
Desmosome disassembly in response to pemphigus vulgaris IgG occurs in distinct phases and can be reversed by expression of exogenous Dsg3.
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DOI：
10.1038/jid.2010.389
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发表时间：
2011-03
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影响因子：
--
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中科院分区：
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寻常型天疱疮（Pemphigus vulgaris， PV）是一种表皮起疱性疾病，由针对桥粒钙粘蛋白-3 （Dsg3）的抗体引起。PV IgG破坏粘附的机制尚不完全清楚。为了解决这个问题，我们利用原代人角质形成细胞和患者IgG来定义PV IgG引发的形态学、生化和功能变化。桥粒分解分为三个阶段。对固定和活的角质形成细胞的分析表明，PV IgG可引起Dsg3的快速内化，这可能源于Dsg3的非连接池。随后，Dsg3和其他桥粒体成分重新排列成垂直于细胞接触的线性阵列。位于细胞表面的Dsg3复合物在被释放到细胞质囊泡室之前，沿着这些阵列逆行运输。Dsg3分布的这些变化随后是洗涤剂不溶性Dsg3池的耗尽和细胞粘附强度的损失。重要的是，这一分解过程可以通过表达外源Dsg3来阻止，从而驱动Dsg3的生物合成和桥粒组装。这些数据支持PV IgG通过内吞途径改变Dsg3组装到桥粒的动力学和Dsg3细胞表面池的周转，从而导致细胞粘附丧失的模型。
Pemphigus vulgaris (PV) is an epidermal blistering disorder caused by antibodies directed against the desmosomal cadherin desmoglein-3 (Dsg3). The mechanism by which PV IgG disrupt adhesion is not fully understood. To address this issue, primary human keratinocytes and patient IgG were utilized to define the morphological, biochemical and functional changes triggered by PV IgG. Three phases of desmosome disassembly were distinguished. Analysis of fixed and living keratinocytes demonstrated that PV IgG cause rapid Dsg3 internalization which likely originates from a non-junctional pool of Dsg3. Subsequently, Dsg3 and other desmosomal components rearrange into linear arrays that run perpendicular to cell contacts. Dsg3 complexes localized at the cell surface are transported in a retrograde fashion along these arrays before being released into cytoplasmic vesicular compartments. These changes in Dsg3 distribution are followed by depletion of detergent insoluble Dsg3 pools and by the loss of cell adhesion strength. Importantly, this process of disassembly can be prevented by expressing exogenous Dsg3, thereby driving Dsg3 biosynthesis and desmosome assembly. These data support a model in which PV IgG cause the loss of cell adhesion by altering the dynamics of Dsg3 assembly into desmosomes and the turnover of cell surface pools of Dsg3 through endocytic pathways.
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