Melbourne Dental School & Oral Health CRC, The University of Melbourne , Melbourne , Australia .
Autoimmunity. 2014 Mar;47(2):134-40. doi: 10.3109/08916934.2013.866100. Epub 2013 Dec 16.
The cell adhesion molecule plakophilin 3 (Pkp3) plays an essential role in the maintenance of skin integrity and is targeted in certain autoimmune conditions. In one example, we have shown that Pkp3 is instrumental in mediating the discohesive effects of sera from patients with pemphigus vulgaris (PV), a life-threatening autoimmune disease that targets intercellular adhesion in the epidermis. In the present study, we determine the effect of PV autoimmune globulin (PV IgG) on Pkp3 in an in-vitro model of PV. We demonstrate that Pkp3 becomes tyrosine phosphorylated as early as 30 min upon binding of PV IgG to keratinocyte surface and eventually detaches from its binding partner desmoglein 3 (Dsg3). In parallel, Pkp3 is depleted from the membrane (Triton X-soluble) fraction and accumulates in the cytoplasm within 240 min of incubation with PV IgG. Inhibition of Pkp3 phosphorylation by a Src inhibitor attenuates the discohesive effects of PV IgG. Taken together, the data demonstrate that activation of Src-kinase signalling is crucial for PV acantholysis and acts, at least in part, via phosphorylation of the adaptor protein Pkp3.
细胞黏附分子斑联蛋白 3（Pkp3）在维持皮肤完整性方面发挥着重要作用，并且是某些自身免疫性疾病的作用靶点。例如，我们已经表明 Pkp3 在介导寻常型天疱疮（PV）患者血清的离散效应中起着重要作用，寻常型天疱疮是一种危及生命的自身免疫性疾病，其靶标是表皮细胞间的黏附。在本研究中，我们在 PV 的体外模型中确定了 PV 自身免疫球蛋白（PV IgG）对 Pkp3 的影响。我们证明，在 PV IgG 与角质形成细胞表面结合后，Pkp3 最早在 30 分钟时发生酪氨酸磷酸化，最终与其结合伙伴桥粒芯糖蛋白 3（Dsg3）分离。同时，在与 PV IgG 孵育 240 分钟内，Pkp3 从膜（Triton X 可溶性）部分耗尽，并在细胞质中积累。Src 抑制剂抑制 Pkp3 磷酸化可减弱 PV IgG 的离散作用。总之，这些数据表明 Src 激酶信号的激活对于 PV 棘层松解至关重要，并且至少部分通过衔接蛋白 Pkp3 的磷酸化起作用。
