Department of Biology, Division of Microbiology, University of Erlangen-Nuremberg, Erlangen, Germany.
Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
Cell Host Microbe. 2017 Oct 11;22(4):552-560.e5. doi: 10.1016/j.chom.2017.09.005.
The Helicobacter pylori (Hp) type IV secretion system (T4SS) forms needle-like pili, whose binding to the integrin-β receptor results in injection of the CagA oncoprotein. However, the apical surface of epithelial cells is exposed to Hp, whereas integrins are basolateral receptors. Hence, the mechanism of CagA delivery into polarized gastric epithelial cells remains enigmatic. Here, we demonstrate that T4SS pilus formation during infection of polarized cells occurs predominantly at basolateral membranes, and not at apical sites. Hp accomplishes this by secreting another bacterial protein, the serine protease HtrA, which opens cell-to-cell junctions through cleaving epithelial junctional proteins including occludin, claudin-8, and E-cadherin. Using a genetic system expressing a peptide inhibitor, we demonstrate that HtrA activity is necessary for paracellular transmigration of Hp across polarized cell monolayers to reach basolateral membranes and inject CagA. The contribution of this unique signaling cascade to Hp pathogenesis is discussed.
幽门螺杆菌（Hp）的 IV 型分泌系统（T4SS）形成针状菌毛，其与整合素-β受体的结合导致 CagA 癌蛋白的注射。然而，上皮细胞的顶端表面暴露于 Hp，而整合素是基底外侧受体。因此，CagA 递送至极化胃上皮细胞的机制仍然是神秘的。在这里，我们证明在极化细胞感染期间 T4SS 菌毛的形成主要发生在基底外侧膜上，而不是在顶端部位。Hp 通过分泌另一种细菌蛋白丝氨酸蛋白酶 HtrA 来实现这一点，该蛋白通过切割包括紧密连接蛋白、claudin-8 和 E-钙粘蛋白在内的上皮连接蛋白来打开细胞间连接。使用表达肽抑制剂的遗传系统，我们证明 HtrA 活性对于 Hp 穿过极化细胞单层到达基底外侧膜并注射 CagA 的旁细胞迁移是必需的。讨论了这种独特的信号级联反应对 Hp 发病机制的贡献。
