Desmosome signaling - Inhibition of p38MAPK prevents pemphigus vulgaris IgG-induced cytoskeleton reorganization
Desmosome signaling - Inhibition of p38MAPK prevents pemphigus vulgaris IgG-induced cytoskeleton reorganization
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DOI：
10.1074/jbc.m501365200
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发表时间：
2005-06-24
影响因子：
4.8
通讯作者：
Rubenstein, DS
中科院分区：
文献类型：
--
作者：
Berkowitz, P;Hu, PQ;Rubenstein, DS
在人类自身免疫性起泡疾病寻常天疱疮（PV）中，致病性抗体结合桥粒钙粘蛋白桥粒芯糖蛋白-3（dsg 3），导致表皮细胞-细胞脱离（棘层松解）。致病性PV dsg 3自身抗体用于启动人角质形成细胞培养物中的桥粒信号传导。热休克蛋白27（HSP 27）和p38 MAPK被鉴定为响应PV IgG而快速磷酸化的蛋白质。抑制p38 MAPK活性可阻止PV IgG诱导的HSP 27磷酸化、角蛋白丝收缩和肌动蛋白重组。这些观察结果表明，PV IgG与dsg 3结合激活桥粒信号转导级联，导致（i）p38 MAPK和HSP 27磷酸化和（ii）细胞骨架重组，支持PV IgG诱导的棘层松解中信号传导的机制作用。通过抑制p38 MAPK和HSP 27磷酸化靶向桥粒信号传导可能为PV和其他桥粒相关水疱性疾病提供新的治疗方法。
In the human autoimmune blistering disease pemphigus vulgaris (PV) pathogenic antibodies bind the desmosomal cadherin desmoglein-3 (dsg3), causing epidermal cell-cell detachment ( acantholysis). Pathogenic PV dsg3 autoantibodies were used to initiate desmosome signaling in human keratinocyte cell cultures. Heat shock protein 27 (HSP27) and p38MAPK were identified as proteins rapidly phosphorylated in response to PV IgG. Inhibition of p38MAPK activity prevented PV IgG-induced HSP27 phosphorylation, keratin filament retraction, and actin reorganization. These observations suggest that PV IgG binding to dsg3 activates desmosomal signal transduction cascades leading to (i) p38MAPK and HSP27 phosphorylation and (ii) cytoskeletal reorganization, supporting a mechanistic role for signaling in PV IgG-induced acantholysis. Targeting desmosome signaling via inhibition of p38MAPK and HSP27 phosphorylation may provide novel treatments for PV and other desmosome-associated blistering diseases.