PHD3 Stabilizes the Tight Junction Protein Occludin and Protects Intestinal Epithelial Barrier Function
PHD3 Stabilizes the Tight Junction Protein Occludin and Protects Intestinal Epithelial Barrier Function
复制标题
PHD3 稳定紧密连接蛋白 Occludin 并保护肠上皮屏障功能
DOI：
10.1074/jbc.m115.653584
复制
发表时间：
2015-08-14
影响因子：
4.8
通讯作者：
Fang, Jing
中科院分区：
文献类型：
--
作者：
Chen, Ying;Zhang, Hai-Sheng;Fang, Jing
脯氨酰羟化酶结构域蛋白（PHDs）控制细胞对缺氧的适应。PHD被发现参与炎症性肠病（IBD）;然而，PHD家族成员PHD 3在IBD中的确切作用仍然未知。我们在这里表明，PHD 3在维持肠上皮屏障功能中起着关键作用。我们发现，肠上皮细胞中Phd 3的基因消除导致小鼠自发性结肠炎。PHD 3的缺失降低了紧密连接蛋白occludin的水平，导致肠上皮屏障功能的失败。进一步的研究表明，PHD 3通过阻止E3连接酶Itch和occludin之间的相互作用，以不依赖于羟化酶的方式稳定occludin。对人溃疡性结肠炎患者的活检检查表明，PHD 3随着疾病严重程度而降低，表明PHD 3下调与该疾病的进展相关。我们发现PHD 3保护肠上皮屏障功能，并揭示了PHD 3在稳定闭合蛋白中的不依赖于羟化酶的功能。这些发现可能有助于开辟IBD治疗策略的途径。
Prolyl hydroxylase domain proteins (PHDs) control cellular adaptation to hypoxia. PHDs are found involved in inflammatory bowel disease (IBD); however, the exact role of PHD3, a member of the PHD family, in IBD remains unknown. We show here that PHD3 plays a critical role in maintaining intestinal epithelial barrier function. We found that genetic ablation of Phd3 in intestinal epithelial cells led to spontaneous colitis in mice. Deletion of PHD3 decreases the level of tight junction protein occludin, leading to a failure of intestinal epithelial barrier function. Further studies indicate that PHD3 stabilizes occludin by preventing the interaction between the E3 ligase Itch and occludin, in a hydroxylase-independent manner. Examination of biopsy of human ulcerative colitis patients indicates that PHD3 is decreased with disease severity, indicating that PHD3 down-regulation is associated with progression of this disease. We show that PHD3 protects intestinal epithelial barrier function and reveal a hydroxylase-independent function of PHD3 in stabilizing occludin. These findings may help open avenues for developing a therapeutic strategy for IBD.