Pemphigus vulgaris IgG-induced desmoglein-3 endocytosis and desmosomal disassembly are mediated by a clathrin- and dynamin-independent mechanism
Pemphigus vulgaris IgG-induced desmoglein-3 endocytosis and desmosomal disassembly are mediated by a clathrin- and dynamin-independent mechanism
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DOI：
10.1074/jbc.m710046200
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发表时间：
2008-06-27
影响因子：
4.8
通讯作者：
Kowalczyk, Andrew P.
中科院分区：
文献类型：
--
作者：
Delva, Emmanuella;Jennings, Jean Marie;Kowalczyk, Andrew P.
寻常型天疱疮（PV）是一种以口腔粘膜糜烂和表皮水疱为特征的危及生命的自身免疫性疾病。产生的自身抗体靶向桥粒钙粘蛋白桥粒芯糖蛋白-3（Dsg 3）。先前的研究表明，在PV IgG结合后，Dsg 3被内化并进入内-溶酶体途径，在那里它被降解。为了确定参与PV IgG诱导的Dsg 3内化的内吞机制，将人角质形成细胞与PV IgG孵育，并使用各种工具来干扰不同的内吞途径。PV IgG.Dsg3复合物未能与网格蛋白共定位，网格蛋白和动力蛋白依赖性途径的抑制剂对Dsg 3内化几乎没有影响。相反，胆固醇结合剂，如菲律宾霉素和制霉菌素和酪氨酸激酶抑制剂染料木素显着抑制Dsg 3内化。此外，Dsg 3胞质尾区指定了对这些抑制剂的敏感性。此外，用染料木素抑制Dsg 3内吞作用防止了在PV IgG存在下桥粒的破坏和粘附的丧失。总之，这些结果表明，PV IgG诱导的Dsg 3内化是通过网格蛋白和动力蛋白非依赖性途径介导的，并且Dsg 3内吞作用与PV IgG的致病活性紧密相关。
Pemphigus vulgaris (PV) is a life-threatening autoimmune disease characterized by oral mucosal erosions and epidermal blistering. The autoantibodies generated target the desmosomal cadherin desmoglein-3 (Dsg3). Previous studies demonstrate that upon PV IgG binding, Dsg3 is internalized and enters an endo-lysosomal pathway where it is degraded. To define the endocytic machinery involved in PV IgG-induced Dsg3 internalization, human keratinocytes were incubated with PV IgG, and various tools were used to perturb distinct endocytic pathways. The PV IgG.Dsg3 complex failed to colocalize with clathrin, and inhibitors of clathrin- and dynamin-dependent pathways had little or no effect on Dsg3 internalization. In contrast, cholesterol binding agents such as filipin and nystatin and the tyrosine kinase inhibitor genistein dramatically inhibited Dsg3 internalization. Furthermore, the Dsg3 cytoplasmic tail specified sensitivity to these inhibitors. Moreover, inhibition of Dsg3 endocytosis with genistein prevented disruption of desmosomes and loss of adhesion in the presence of PV IgG. Altogether, these results suggest that PV IgG-induced Dsg3 internalization is mediated through a clathrin- and dynamin-independent pathway and that Dsg3 endocytosis is tightly coupled to the pathogenic activity of PV IgG.