title: Competitive binding of CUGBP1 and HuR to occludin mRNA controls its translation and modulates epithelial barrier function.
abstract: RNA-binding proteins CUG-binding protein 1 (CUGBP1) and HuR are highly expressed in epithelial tissues and modulate the stability and translation of target mRNAs. Here we present evidence that CUGBP1 and HuR jointly regulate the translation of occludin and play a crucial role in the maintenance of tight junction (TJ) integrity in the intestinal epithelial cell monolayer. CUGBP1 and HuR competed for association with the same occludin 3'-untranslated region element and regulated occludin translation competitively and in opposite directions. CUGBP1 overexpression decreased HuR binding to occludin mRNA, repressed occludin translation, and compromised the TJ barrier function, whereas HuR overexpression inhibited CUGBP1 association with occludin mRNA and promoted occludin translation, thereby enhancing the barrier integrity. Repression of occludin translation by CUGBP1 was due to the colocalization of CUGBP1 and tagged occludin RNA in processing bodies (P-bodies), and this colocalization was prevented by HuR overexpression. These findings indicate that CUGBP1 represses occludin translation by increasing occludin mRNA recruitment to P-bodies, whereas HuR promotes occludin translation by blocking occludin mRNA translocation to P-bodies via the displacement of CUGBP1.
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Ting-Xi
authors.initials: TX
authors.lastname: Yu
authors.forename: Jaladanki N
authors.initials: JN
authors.lastname: Rao
authors.forename: Tongtong
authors.initials: T
authors.lastname: Zou
authors.forename: Lan
authors.initials: L
authors.lastname: Liu
authors.forename: Lan
authors.initials: L
authors.lastname: Xiao
authors.forename: Miao
authors.initials: M
authors.lastname: Ouyang
authors.forename: Shan
authors.initials: S
authors.lastname: Cao
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions; D001483:Base Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D000067879:CELF1 Protein; D018938:Caco-2 Cells; D051959:ELAV Proteins / Q000378:metabolism*; D017097:Electric Impedance; D004847:Epithelial Cells / Q000502:physiology*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D006801:Humans; D007422:Intestines / Q000166:cytology / Q000502:physiology; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D062793:Occludin / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019108:Tight Junctions / Q000502:physiology
chemical_list: D020413:3' Untranslated Regions; D000067879:CELF1 Protein; C102843:CELF1 protein, human; D051959:ELAV Proteins; C568985:OCLN protein, human; D062793:Occludin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D049410:Luciferases, Renilla