Jin Xiaowei, Rosenbohm Jordan, Kim Eunju, Safa Bahareh Tajvidi, Moghaddam Amir Ostadi, Seiffert-Sinha Kristina, Leiker Merced, Jones Elijah, Zhai Haiwei, Baddam Sindora R, Minnick Grayson, Huo Yucheng, Wahl James K, Meng Fanben, Huang Changjin, Lim Jung Yul, Conway Daniel E, Sinha Animesh A, Yang Ruiguo
Department of Mechanical and Materials Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
Department of Biomedical Engineering, Michigan State University, East Lansing, MI 48823, USA.
iScience. 2025 Jul 9;28(8):113081. doi: 10.1016/j.isci.2025.113081. eCollection 2025 Aug 15.
Autoantibody binding to keratinocyte surface antigens, primarily desmoglein 3 (Dsg3) in the desmosome, leads to dissociation of cell-cell adhesions in pemphigus vulgaris. Much of the biophysical transformations after antibody binding remain underexplored. It is unclear how tensions in desmosomes and cell-cell adhesion structures change in response to antibodies, and how the altered tensional states translate to cellular responses. Here, using fluorescence resonance energy transfer-based tension sensors and traction force microscopy, we observed tension loss at Dsg3 and the entire cell-cell adhesion after antibody binding, along with potentially compensatory increase in junctional traction force at cell-extracellular matrix adhesions. Our data also indicate that this tension loss is mediated by RhoA inhibition at cell-cell contacts and can be partially restored by altering cell contractility. Collectively, these findings shed light on the biophysical mechanisms governing cell-cell interactions under autoimmune conditions, and may lead to therapies aimed at restoring tensional balance at cell-cell adhesions.
自身抗体与角质形成细胞表面抗原结合，主要是桥粒中的桥粒芯糖蛋白3（Dsg3），导致寻常型天疱疮中细胞间黏附的解离。抗体结合后的许多生物物理转变仍未得到充分研究。目前尚不清楚桥粒和细胞间黏附结构中的张力如何响应抗体而变化，以及改变的张力状态如何转化为细胞反应。在这里，我们使用基于荧光共振能量转移的张力传感器和牵引力显微镜，观察到抗体结合后Dsg3和整个细胞间黏附处的张力丧失，以及细胞与细胞外基质黏附处的连接牵引力可能出现的代偿性增加。我们的数据还表明，这种张力丧失是由细胞间接触处的RhoA抑制介导的，并且可以通过改变细胞收缩性而部分恢复。这些发现共同揭示了自身免疫条件下控制细胞间相互作用的生物物理机制，并可能导致旨在恢复细胞间黏附张力平衡的治疗方法。
