Immunobiology and Dermatology, UCL Institute of Child Health, London, UK; Prostate Cancer Research Group, Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.
Exp Dermatol. 2013 Nov;22(11):754-6. doi: 10.1111/exd.12234.
Epidermal barrier acquisition during late mammalian development is a prerequisite for terrestrial existence. Over a 24-h period, the epidermis goes from being a barrier-deficient, dye permeable epithelium to a barrier-competent epithelium. We have previously shown that Akt signalling is necessary for barrier acquisition in the mouse and that the protein phosphatase 2A regulatory subunit Ppp2r2a causes barrier acquisition by dephosphorylation of cJun. Here, we demonstrate that there is transient interaction between the gap junction protein Connexin 43 (Cx43) and Zonula occludins-1 (Zo-1) during epidermal barrier acquisition. Ppp2r2a knockdown prevented plasma membrane co-localisation and interaction between the two proteins. Ppp2r2a knockdown also increased phosphorylation at Serine 368 of Connexin 43. Cx43 phosphorlyation at Serine368 occurred just prior to the interaction between Connexin 43 and Zo-1. We therefore propose a model in which Ppp2r2a is required both for the initial interaction between Zo-1 and Cx43 and the consequent dephosphorylation of Connexin 43, preventing interaction of Zo-1 and allowing Zo-1 to initiate tight junction formation and barrier acquisition.
哺乳动物晚期表皮屏障的获得是陆地生存的先决条件。在 24 小时内，表皮从一个屏障缺陷、染料可渗透的上皮细胞转变为一个具有屏障功能的上皮细胞。我们之前已经表明，Akt 信号通路对于小鼠表皮屏障的获得是必需的，而蛋白磷酸酶 2A 的调节亚基 Ppp2r2a 通过使 cJun 去磷酸化来导致屏障的获得。在这里，我们证明在表皮屏障获得过程中，间隙连接蛋白 Connexin 43 (Cx43) 和 Zonula occludins-1 (Zo-1) 之间存在短暂的相互作用。Ppp2r2a 的敲低阻止了这两种蛋白在质膜上的共定位和相互作用。Ppp2r2a 的敲低也增加了 Connexin 43 的丝氨酸 368 的磷酸化。Connexin 43 的 Ser368 磷酸化发生在 Connexin 43 与 Zo-1 相互作用之前。因此，我们提出了一个模型，即 Ppp2r2a 既需要 Zo-1 和 Cx43 之间的初始相互作用，也需要随后的 Connexin 43 的去磷酸化，以防止 Zo-1 的相互作用，并允许 Zo-1 启动紧密连接的形成和屏障的获得。
