title: PHD3 Stabilizes the Tight Junction Protein Occludin and Protects Intestinal Epithelial Barrier Function.
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.
authors.affiliation: From the Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: From the Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Hai-Sheng
authors.initials: HS
authors.lastname: Zhang
authors.affiliation: the Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut 06030.
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Fong
authors.affiliation: the Department of Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai 200030, China.
authors.forename: Qiu-Lei
authors.initials: QL
authors.lastname: Xi
authors.affiliation: the Department of Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai 200030, China.
authors.forename: Guo-Hao
authors.initials: GH
authors.lastname: Wu
authors.affiliation: the Department of Pathology, Changhai Hospital, the Second Military Medical University, Shanghai 200433, China.
authors.forename: Chen-Guang
authors.initials: CG
authors.lastname: Bai
authors.affiliation: the Department of Pathology, Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital and Zhejiang Cancer Center, Hangzhou 310022, China, and.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Ling
authors.affiliation: From the Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.affiliation: From the Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Xu
authors.affiliation: From the Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Qin
authors.affiliation: From the Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Tang-Long
authors.initials: TL
authors.lastname: Yuan
authors.affiliation: From the Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Sun
authors.affiliation: From the Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, the Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021 China jfang@sibs.ac.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
mesh_terms: D000818:Animals; D003092:Colitis / Q000235:genetics / Q000517:prevention & control; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D062793:Occludin / Q000502:physiology*; D011393:Procollagen-Proline Dioxygenase / Q000502:physiology*
chemical_list: D062793:Occludin; C568986:Ocln protein, mouse; C522722:PHD3 protein, mouse; D011393:Procollagen-Proline Dioxygenase
keywords: cell biology; colitis; inflammatory bowel disease (IBD); intestinal epithelium; occludin; prolyl hydroxylase; tight junction