Chen Ying, Zhang Hai-Sheng, Fong Guo-Hua, Xi Qiu-Lei, Wu Guo-Hao, Bai Chen-Guang, Ling Zhi-Qiang, Fan Li, Xu Yi-Ming, Qin Yan-Qing, Yuan Tang-Long, Sun Heng, Fang Jing
From the Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
the Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut 06030.
J Biol Chem. 2015 Aug 14;290(33):20580-9. doi: 10.1074/jbc.M115.653584. Epub 2015 Jun 29.
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.
脯氨酰羟化酶结构域蛋白（PHDs）控制细胞对缺氧的适应性。已发现PHDs与炎症性肠病（IBD）有关；然而，PHD家族成员之一的PHD3在IBD中的确切作用仍不清楚。我们在此表明，PHD3在维持肠道上皮屏障功能中起关键作用。我们发现，肠道上皮细胞中Phd3的基因缺失导致小鼠出现自发性结肠炎。PHD3的缺失会降低紧密连接蛋白闭合蛋白的水平，导致肠道上皮屏障功能失效。进一步研究表明，PHD3通过以一种不依赖羟化酶的方式阻止E3连接酶Itch与闭合蛋白之间的相互作用来稳定闭合蛋白。对人类溃疡性结肠炎患者活检样本的检查表明，PHD3随着疾病严重程度的增加而降低，这表明PHD3下调与该疾病的进展有关。我们证明了PHD3保护肠道上皮屏障功能，并揭示了PHD3在稳定闭合蛋白方面不依赖羟化酶的功能。这些发现可能有助于为开发IBD的治疗策略开辟道路。
