PDF(Pubmed)
Abstract：
Binding of autoantibodies to keratinocyte surface antigens, primarily desmoglein 3 (Dsg3) of the desmosomal complex, leads to the dissociation of cell-cell adhesion in the blistering disorder pemphigus vulgaris (PV). After the initial disassembly of desmosomes, cell-cell adhesions actively remodel in association with the cytoskeleton and focal adhesions. Growing evidence highlights the role of adhesion mechanics and mechanotransduction at cell-cell adhesions in this remodeling process, as their active participation may direct autoimmune pathogenicity. However, a large part of the biophysical transformations after antibody binding remains underexplored. Specifically, it is unclear how tension in desmosomes and cell-cell adhesions changes in response to antibodies, and how the altered tensional states translate to cellular responses. Here, we showed a tension loss at Dsg3 using fluorescence resonance energy transfer (FRET)-based tension sensors, a tension loss at the entire cell-cell adhesion, and a potentially compensatory increase in junctional traction force at cell-extracellular matrix adhesions after PV antibody binding. Further, our data indicate that this tension loss is mediated by the inhibition of RhoA at cell-cell contacts, and the extent of RhoA inhibition may be crucial in determining the severity of pathogenicity among different PV antibodies. More importantly, this tension loss can be partially restored by altering actomyosin based cell contractility. Collectively, these findings provide previously unattainable details in our understanding of the mechanisms that govern cell-cell interactions under physiological and autoimmune conditions, which may open the window to entirely new therapeutics aimed at restoring physiological balance to tension dynamics that regulates the maintenance of cell-cell adhesion.
摘要：
自身抗体与角质形成细胞表面抗原的结合，主要是桥粒复合物的桥粒3（Dsg3），导致寻常性天疱疮（PV）中细胞-细胞粘附的解离。在桥粒最初解体后，与细胞骨架和粘着斑相关的细胞-细胞粘附积极地重塑。越来越多的证据强调了粘附力学和机械转导在细胞-细胞粘附过程中的作用。因为它们的积极参与可能指导自身免疫致病性。然而,抗体结合后的大部分生物物理转化仍未充分开发。具体来说,尚不清楚桥粒和细胞间粘连的张力如何响应抗体而发生变化，以及改变的张力状态如何转化为细胞反应。这里,我们使用基于荧光共振能量转移（FRET）的张力传感器显示了Dsg3的张力损失，整个细胞-细胞粘附的张力损失，PV抗体结合后，细胞-细胞外基质粘连处的连接牵引力可能代偿性增加。Further,我们的数据表明，这种张力损失是由细胞-细胞接触时RhoA的抑制介导的，RhoA抑制的程度对于确定不同PV抗体之间致病性的严重程度可能是至关重要的。更重要的是,这种张力损失可以通过改变基于肌动球蛋白的细胞收缩性来部分恢复。总的来说，这些发现为我们理解在生理和自身免疫条件下控制细胞-细胞相互作用的机制提供了以前无法实现的细节，这可能为旨在恢复生理平衡到调节细胞-细胞粘附维持的张力动力学的全新疗法打开窗口。
