细胞对机械力的反应方式会严重影响上皮内稳态,细胞之间力平衡的局部变化和组织水平力的改变.1特殊的细胞-细胞粘附与细胞骨架的耦合为上皮提供了不同的应对机械应激的策略2,3,4当相关的中间丝(IFs)2,3变硬时,端粒赋予组织弹性以响应应变,5,6,7,8,9,10,11,而与粘附连接(AJ)处的E-钙黏着蛋白装置12,13相关的机械转导通过RhoA信号传导主动调节肌动球蛋白。尽管桥粒和AJ对上皮的机械稳态做出了补充贡献,6,8越来越多的证据表明这些细胞骨架粘附系统可以在功能和生物化学上相互作用。8,14,15,16,17,18,19,20我们现在报道了由desmoplakin(DP)整合的桥粒-IF系统促进了AJ的主动张力感应,以实现上皮内稳态。当向上皮单层施加张力时,DP功能对于激活AJ上的机械敏感性RhoA信号是必需的。这种作用需要DP将IF锚定到桥粒上,并将肌张力素(DST)细胞连接蛋白招募到顶端。DPRNAi通过增加的单层张力降低了施加于钙黏着蛋白复合物的机械负荷。与降低的机械信号强度一致,DPRNAi损害了激活RhoA的肌球蛋白VI-E-钙粘蛋白机械传感器的组装。因此,集成的DP-IF系统通过增强传递给E-cadherin的组织张力的机械负载来支持AJ机械传导。这种串扰对于通过顶端挤压有效消除凋亡的上皮细胞是必要的,证明了它对上皮稳态的贡献。
Epithelial homeostasis can be critically influenced by how cells respond to mechanical forces, both local changes in force balance between cells and altered tissue-level forces.1 Coupling of specialized cell-cell adhesions to their cytoskeletons provides epithelia with diverse strategies to respond to mechanical stresses.2,3,4 Desmosomes confer tissue resilience when their associated intermediate filaments (IFs)2,3 stiffen in response to strain,5,6,7,8,9,10,11 while mechanotransduction associated with the E-cadherin apparatus12,13 at adherens junctions (AJs) actively modulates actomyosin by RhoA signaling. Although desmosomes and AJs make complementary contributions to mechanical homeostasis in epithelia,6,8 there is increasing evidence to suggest that these cytoskeletal-adhesion systems can interact functionally and biochemically.8,14,15,16,17,18,19,20 We now report that the desmosome-IF system integrated by
desmoplakin (DP) facilitates active tension sensing at AJs for epithelial homeostasis. DP function is necessary for mechanosensitive RhoA signaling at AJs to be activated when tension was applied to epithelial monolayers. This effect required DP to anchor IFs to desmosomes and recruit the dystonin (DST) cytolinker to apical junctions. DP RNAi reduced the mechanical load that was applied to the cadherin complex by increased monolayer tension. Consistent with reduced mechanical signal strength, DP RNAi compromised assembly of the Myosin VI-E-cadherin mechanosensor that activates RhoA. The integrated DP-IF system therefore supports AJ mechanotransduction by enhancing the mechanical load of tissue tension that is transmitted to E-cadherin. This crosstalk was necessary for efficient elimination of apoptotic epithelial cells by apical extrusion, demonstrating its contribution to epithelial homeostasis.