title: Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function.
abstract: Occludin is a transmembrane tight junction (TJ) protein that plays an important role in TJ assembly and regulation of the epithelial barrier function, but the mechanisms underlying its post-transcriptional regulation are unknown. The RNA-binding protein HuR modulates the stability and translation of many target mRNAs. Here, we investigated the role of HuR in the regulation of occludin expression and therefore in the intestinal epithelial barrier function. HuR bound the 3'-untranslated region of the occludin mRNA and enhanced occludin translation. HuR association with the occludin mRNA depended on Chk2-dependent HuR phosphorylation. Reduced HuR phosphorylation by Chk2 silencing or by reduction of Chk2 through polyamine depletion decreased HuR-binding to the occludin mRNA and repressed occludin translation, whereas Chk2 overexpression enhanced (HuR/occludin mRNA) association and stimulated occludin expression. In mice exposed to septic stress induced by cecal ligation and puncture, Chk2 levels in the intestinal mucosa decreased, associated with an inhibition of occludin expression and gut barrier dysfunction. These results indicate that HuR regulates occludin mRNA translation through Chk2-dependent HuR phosphorylation and that this influence is crucial for maintenance of the epithelial barrier integrity in the intestinal tract.
authors: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore Street, Baltimore, MD 21201, USA.
authors: Ting-Xi
authors: TX
authors: Yu
authors: Peng-Yuan
authors: PY
authors: Wang
authors: Jaladanki N
authors: JN
authors: Rao
authors: Tongtong
authors: T
authors: Zou
authors: Lan
authors: L
authors: Liu
authors: Lan
authors: L
authors: Xiao
authors: Myriam
authors: M
authors: Gorospe
authors: Jian-Ying
authors: JY
authors: Wang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2; D051959:ELAV Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D062793:Occludin; D010766:Phosphorylation; D011073:Polyamines / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018805:Sepsis / Q000201:enzymology / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D051959:ELAV Proteins; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; C568987:Ocln protein, rat; D011073:Polyamines; D012333:RNA, Messenger; D064447:Checkpoint Kinase 2; C578633:Chek2 protein, mouse; C578632:Chek2 protein, rat; D017346:Protein Serine-Threonine Kinases