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PHD3 Stabilizes the Tight Junction Protein Occludin and Protects Intestinal Epithelial Barrier Function
Authors:Ying Chen  Hai-Sheng Zhang  Guo-Hua Fong  Qiu-Lei Xi  Guo-Hao Wu  Chen-Guang Bai  Zhi-Qiang Ling  Li Fan  Yi-Ming Xu  Yan-Qing Qin  Tang-Long Yuan  Heng Sun  Jing Fang
Abstract: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.
Keywords:cell biology  colitis  inflammatory bowel disease (IBD)  intestinal epithelium  tight junction  occludin  prolyl hydroxylase
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