Pemphigus vulgaris autoimmune globulin induces Src-dependent tyrosine-phosphorylation of plakophilin 3 and its detachment from desmoglein 3
Pemphigus vulgaris autoimmune globulin induces Src-dependent tyrosine-phosphorylation of plakophilin 3 and its detachment from desmoglein 3
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DOI：
10.3109/08916934.2013.866100
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发表时间：
2014-03-01
期刊：
影响因子：
3.5
通讯作者：
Prime, Stephen S.
中科院分区：
文献类型：
--
作者：
Cirillo, Nicola;AlShwaimi, Emad;Prime, Stephen S.
细胞粘附分子亲血小板蛋白3 （Pkp3）在维持皮肤完整性中起着至关重要的作用，并且在某些自身免疫性疾病中是靶向的。在一个例子中，我们已经证明Pkp3在介导寻常型天疱疮（PV）患者血清的解粘作用中发挥了重要作用，寻常型天疱疮是一种以表皮细胞间粘连为目标的危及生命的自身免疫性疾病。在本研究中，我们在体外PV模型中确定PV自身免疫球蛋白（PV IgG）对Pkp3的影响。我们证明Pkp3在PV IgG与角质形成细胞表面结合后30分钟就会发生酪氨酸磷酸化，并最终从其结合伙伴粘粒蛋白3 （Dsg3）上分离。与此同时，Pkp3从膜（Triton x可溶性）部分中消失，并在与PV IgG孵育240分钟内在细胞质中积累。Src抑制剂抑制Pkp3磷酸化可减弱PV IgG的解粘作用。综上所述，这些数据表明，src激酶信号的激活对于PV棘醇解至关重要，并且至少在一定程度上通过接合蛋白Pkp3的磷酸化起作用。
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.