Epithelial Gasdermin D shapes the host-microbial interface by driving mucus layer formation
Epithelial Gasdermin D shapes the host-microbial interface by driving mucus layer formation
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上皮细胞 Gasdermin D 通过驱动粘液层形成来塑造宿主-微生物界面
DOI：
10.1126/sciimmunol.abk2092
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发表时间：
2022-02-01
影响因子：
24.8
通讯作者：
Wang, Di
中科院分区：
文献类型：
--
作者：
Zhang, Jian;Yu, Qianzhou;Wang, Di
杯状细胞及其主要分泌产物粘液在协调结肠宿主-微生物相互作用以帮助维持肠道稳态方面发挥着至关重要的作用。然而，这种杯状细胞诱导的粘液分泌背后的精确细胞内机制仍然知之甚少。 Gasdermin D (GSDMD) 是一种最近发现的成孔效应蛋白，可导致细胞焦亡，这是一种在各种病理生理条件下发生的溶解性促炎细胞死亡类型。在这里，我们揭示了 GSDMD 在杯状细胞粘蛋白分泌和粘液层形成中的意想不到的功能。肠上皮细胞中 Gsdmd 的特异性缺失 (Delta IEC) 导致粘液分泌消失，并伴随粘液层的损失。 Gsdmd(Delta IEC) 小鼠的结肠粘液层受损，其特征是宿主-微生物界面受到干扰，并且肠道病原体从粘膜表面的清除效率低下。从机制上讲，刺激杯状细胞会激活半胱天冬酶，通过产生活性氧来处理 GSDMD；反过来，这种激活的 GSDMD 通过钙离子依赖性 scinderin 介导的皮质 F-肌动蛋白分解驱动粘蛋白分泌，这是颗粒胞吐作用的关键步骤。这项研究将上皮 GSDMD 与分泌颗粒胞吐途径联系起来，并强调了其在塑造肠道粘膜稳态中的生理非焦亡作用。
Goblet cells and their main secretory product, mucus, play crucial roles in orchestrating the colonic host-microbe interactions that help maintain gut homeostasis. However, the precise intracellular machinery underlying this goblet cell-induced mucus secretion remains poorly understood. Gasdermin D (GSDMD) is a recently identified pore-forming effector protein that causes pyroptosis, a lytic proinflammatory type of cell death occurring during various pathophysiological conditions. Here, we reveal an unexpected function of GSDMD in goblet cell mucin secretion and mucus layer formation. Specific deletion of Gsdmd in intestinal epithelial cells (Delta IEC) led to abrogated mucus secretion with a concomitant loss of the mucus layer. This impaired colonic mucus layer in Gsdmd(Delta IEC) mice featured a disturbed host-microbial interface and inefficient clearance of enteric pathogens from the mucosal surface. Mechanistically, stimulation of goblet cells activates caspases to process GSDMD via reactive oxygen species production; in turn, this activated GSDMD drives mucin secretion through calcium ion-dependent scinderin-mediated cortical F-actin disassembly, which is a key step in granule exocytosis.This study links epithelial GSDMD to the secretory granule exocytotic pathway and highlights its physiological nonpyroptotic role in shaping mucosal homeostasis in the gut.