Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Munich, Germany.
Institute of Biology and Translational Center for Regenerative Medicine, Sächsischer Inkubator für klinische Translation, University of Leipzig, Leipzig, Germany.
J Invest Dermatol. 2018 Jan;138(1):121-131. doi: 10.1016/j.jid.2017.08.033. Epub 2017 Sep 9.
Tightly controlled intercellular adhesion is crucial for the integrity and function of the epidermis. The keratin filament cytoskeleton anchors desmosomes, supramolecular complexes required for strong intercellular adhesion. We tested whether keratin filaments control cell adhesion by regulating the adhesive properties of desmosomal cadherins such as desmoglein (Dsg) 3. Atomic force microscopy and fluorescence recovery after photobleaching experiments showed reduced Dsg3 adhesive forces and membrane stability in murine keratinocytes lacking all keratin filaments. Impairment of the actin cytoskeleton also resulted in decreased Dsg3 immobilization but did not affect Dsg3 binding properties, indicating that the latter are exclusively controlled by keratins. Reduced binding forces were dependent on p38 mitogen-activated protein kinase activity, which was deregulated in keratin-deficient cells. In contrast, inhibition of protein kinase C signaling, which is known to be controlled by keratins, promoted and spatially stabilized Dsg3-mediated interactions in the membrane. These results show a previously unreported mechanism for how keratins stabilize intercellular adhesion on the level of single desmosomal adhesion molecules.
紧密控制的细胞间黏附对于表皮的完整性和功能至关重要。角蛋白丝细胞骨架锚定桥粒，这是强细胞间黏附所必需的超分子复合物。我们测试了角蛋白丝是否通过调节桥粒钙黏蛋白（如 desmoglein 3，Dsg3）的黏附特性来控制细胞黏附。原子力显微镜和光漂白后荧光恢复实验表明，缺乏所有角蛋白丝的小鼠角蛋白细胞中 Dsg3 的黏附力和膜稳定性降低。肌动蛋白细胞骨架的损伤也导致 Dsg3 固定减少，但不影响 Dsg3 的结合特性，表明后者仅受角蛋白控制。结合力的降低依赖于 p38 有丝分裂原激活蛋白激酶的活性，而在角蛋白缺陷细胞中，这种活性被失调。相比之下，已知受角蛋白控制的蛋白激酶 C 信号通路的抑制促进并空间稳定了 Dsg3 介导的膜内相互作用。这些结果表明了一种以前未报道的机制，即角蛋白如何稳定单个桥粒黏附分子水平上的细胞间黏附。
