Desmoglein endocytosis and desmosome disassembly are coordinated responses to pemphigus autoantibodies
Desmoglein endocytosis and desmosome disassembly are coordinated responses to pemphigus autoantibodies
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DOI：
10.1074/jbc.m512447200
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发表时间：
2006-03-17
影响因子：
4.8
通讯作者：
Kowalczyk, AP
中科院分区：
文献类型：
--
作者：
Calkins, CC;Setzer, SV;Kowalczyk, AP
桥粒是在皮肤和心脏中突出的粘附性细胞间连接。桥粒功能的丧失与以组织脆性为特征的严重先天性和获得性疾病有关。寻常天疱疮（PV）是一种自身免疫性疾病，其中抗体针对桥粒粘附分子Dsg 3，导致严重的粘膜糜烂和表皮起泡。为了确定Dsg 3自身抗体破坏角质形成细胞粘附的机制，在暴露于PV患者IgG的原代人角质形成细胞中监测PV IgG和各种桥粒组分的命运。PV IgG最初与角质形成细胞表面结合，并与桥粒标志物共定位。在PV IgG结合Dsg 3后6小时内，电子显微镜显示桥粒被显著破坏，角质形成细胞粘附严重受损。免疫荧光分析表明，PV IgG和Dsg 3从细胞表面迅速内化的复合物斑珠蛋白，但不桥粒斑蛋白。Dsg 3内化与角蛋白丝从细胞-细胞边界的收缩有关。此外，内化的PV IgG-Dsg 3复合物与内体和溶酶体的标记物共定位，表明Dsg 3被靶向降解。与这种可能性相一致，生物素化实验表明，可溶性Dsg 3细胞表面池被迅速耗尽，随后是洗涤剂不溶性Dsg 3的损失。这些发现表明Dsg 3内吞作用、角蛋白丝收缩和角质形成细胞-细胞粘附的丧失是对PV IgG的协调应答。
Desmosomes are adhesive intercellular junctions prominent in the skin and heart. Loss of desmosome function is associated with severe congenital and acquired disorders characterized by tissue fragility. Pemphigus vulgaris (PV) is an autoimmune disorder in which antibodies are directed against the desmosomal adhesion molecule Dsg3, resulting in severe mucosal erosions and epidermal blistering. To define the mechanisms by which Dsg3 autoantibodies disrupt keratinocyte adhesion, the fate of PV IgG and various desmosomal components was monitored in primary human keratinocytes exposed to PV patient IgG. PV IgG initially bound to keratinocyte cell surfaces and colocalized with desmosomal markers. Within 6 h after PV IgG binding to Dsg3, electron microscopy revealed that desmosomes were dramatically disrupted and keratinocyte adhesion was severely compromised. Immunofluorescence analysis indicated that PV IgG and Dsg3 were rapidly internalized from the cell surface in a complex with plakoglobin but not desmoplakin. Dsg3 internalization was associated with retraction of keratin filaments from cell-cell borders. Furthermore, the internalized PV IgG-Dsg3 complex colocalized with markers for both endosomes and lysosomes, suggesting that Dsg3 was targeted for degradation. Consistent with this possibility, biotinylation experiments demonstrated that soluble Dsg3 cell surface pools were rapidly depleted followed by loss of detergent-insoluble Dsg3. These findings demonstrate that Dsg3 endocytosis, keratin filament retraction, and the loss of keratinocyte cell-cell adhesion are coordinated responses to PV IgG.