Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, IL 60611, USA.
Am J Pathol. 2010 Dec;177(6):2921-37. doi: 10.2353/ajpath.2010.100397. Epub 2010 Nov 12.
Desmoglein 1 (Dsg1) is a desmosomal cadherin that is essential to epidermal integrity. In the blistering diseases bullous impetigo and staphylococcal scalded-skin syndrome, pathogenesis depends on cleavage of Dsg1 by a bacterial protease, exfoliative toxin A, which removes residues 1 to 381 of the Dsg1 ectodomain. However, the cellular responses to Dsg1 cleavage that precipitate keratinocyte separation to induce blister formation are unknown. Here, we show that ectodomain-deleted Dsg1 (Δ381-Dsg1) mimics the toxin-cleaved cadherin, disrupts desmosomes, and reduces the mechanical integrity of keratinocyte sheets. In addition, we demonstrate that truncated Dsg1 remains associated with its catenin partner, plakoglobin, and causes a reduction in the levels of endogenous desmosomal cadherins in a dose-dependent manner, leading us to hypothesize that plakoglobin sequestration by truncated Dsg1 destabilizes other cadherins. Accordingly, a triple-point mutant of the ectodomain-deleted cadherin, which is uncoupled from plakoglobin, does not impair adhesion, indicating that this interaction is essential to the pathogenic potential of truncated Dsg1. Moreover, we demonstrate that increasing plakoglobin levels rescues cadherin expression, desmosome organization, and functional adhesion in cells expressing Δ381-Dsg1 or treated with exfoliative toxin A. Finally, we report that histone deacetylase inhibition up-regulates desmosomal cadherins and prevents the loss of adhesion induced by Dsg1 truncation. These findings further our understanding of the mechanism of exfoliative toxin-induced pathology and suggest novel strategies to suppress blistering in bulbous impetigo and staphylococcal scalded-skin syndrome.
桥粒芯糖蛋白 1（Dsg1）是一种桥粒钙黏蛋白，对表皮完整性至关重要。在大疱性脓疱病和葡萄球菌性烫伤样皮肤综合征这两种起疱性疾病中，发病机制依赖于细菌蛋白酶——表皮剥脱毒素 A 对 Dsg1 的裂解，该酶会切除 Dsg1 胞外结构域的 1 到 381 个残基。然而，导致角质形成细胞分离引发水疱形成的 Dsg1 裂解所引发的细胞反应尚不清楚。在这里，我们发现缺失胞外结构域的 Dsg1（Δ381-Dsg1）模拟了毒素切割的钙黏蛋白，破坏了桥粒，并降低了角质形成细胞片的机械完整性。此外，我们证明截短的 Dsg1 仍然与它的连环蛋白伴侣桥粒斑蛋白（plakoglobin）相关联，并以剂量依赖性的方式降低内源性桥粒钙黏蛋白的水平，这使我们假设截短的 Dsg1 对桥粒斑蛋白的隔离会使其他钙黏蛋白失稳。因此，缺失胞外结构域的钙黏蛋白的三突变体与桥粒斑蛋白解耦联，不会损害黏附，这表明这种相互作用对于截短的 Dsg1 的致病潜力至关重要。此外，我们证明增加桥粒斑蛋白的水平可以挽救表达 Δ381-Dsg1 或用表皮剥脱毒素 A 处理的细胞中的钙黏蛋白表达、桥粒组织和功能黏附。最后，我们报告组蛋白去乙酰化酶抑制可上调桥粒钙黏蛋白并防止 Dsg1 截短诱导的黏附丧失。这些发现进一步加深了我们对表皮剥脱毒素诱导的病理学机制的理解，并提出了抑制大疱性脓疱病和葡萄球菌性烫伤样皮肤综合征水疱形成的新策略。
