Autophagy Enhances Intestinal Epithelial Tight Junction Barrier Function by Targeting Claudin-2 Protein Degradation
Autophagy Enhances Intestinal Epithelial Tight Junction Barrier Function by Targeting Claudin-2 Protein Degradation
复制标题
DOI：
10.1074/jbc.m114.597492
复制
发表时间：
2015-03-13
影响因子：
4.8
通讯作者：
Ma, Thomas Y.
中科院分区：
文献类型：
--
作者：
Nighot, Prashant K.;Hu, Chien-An Andy;Ma, Thomas Y.
自噬是一种细胞内降解途径，被认为是细胞生存的重要机制。自噬缺陷与许多病理过程有关，包括炎症性肠病。在肠粘膜的先天防御机制中，有缺陷的紧密连接（TJ）屏障已被假定为炎症性肠病的病因和进展中的关键致病因素，通过允许增加抗原渗透。自噬和TJ屏障之间的相互作用尚未被描述。在这项研究中，我们提出了新的发现，自噬增强TJ屏障功能的Caco-2肠上皮细胞。营养饥饿诱导的自噬显著增加了跨上皮电阻，降低了钠/氯的细胞旁渗透率。营养饥饿降低了小分子尿素的细胞旁渗透性，但对大分子尿素没有影响。自噬在调节细胞旁通透性中的作用已被药理学诱导以及自噬的药理学和遗传学抑制所证实。与自噬诱导的细胞旁通透性降低一致，在细胞饥饿后观察到阳离子选择性、成孔TJ蛋白claudin-2的水平显著降低。饥饿减少了膜存在的claudin-2和增加其细胞质，溶酶体定位。因此，我们的数据表明，自噬通过TJ蛋白claudin-2的溶酶体降解选择性地降低上皮TJ离子和小分子的渗透性。
Autophagy is an intracellular degradation pathway and is considered to be an essential cell survival mechanism. Defects in autophagy are implicated in many pathological processes, including inflammatory bowel disease. Among the innate defense mechanisms of intestinal mucosa, a defective tight junction (TJ) barrier has been postulated as a key pathogenic factor in the causation and progression of inflammatory bowel disease by allowing increased antigenic permeation. The cross-talk between autophagy and the TJ barrier has not yet been described. In this study, we present the novel finding that autophagy enhances TJ barrier function in Caco-2 intestinal epithelial cells. Nutrient starvation-induced autophagy significantly increased transepithelial electrical resistance and reduced the ratio of sodium/chloride paracellular permeability. Nutrient starvation reduced the paracellular permeability of small-sized urea but not larger molecules. The role of autophagy in the modulation of paracellular permeability was confirmed by pharmacological induction as well as pharmacological and genetic inhibition of autophagy. Consistent with the autophagy-induced reduction in paracellular permeability, a marked decrease in the level of the cation-selective, pore-forming TJ protein claudin-2 was observed after cell starvation. Starvation reduced the membrane presence of claudin-2 and increased its cytoplasmic, lysosomal localization. Therefore, our data show that autophagy selectively reduces epithelial TJ permeability of ions and small molecules by lysosomal degradation of the TJ protein claudin-2.