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Vol. 19, Issue 9, 3701-3712, September 2008

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JunD Represses Transcription and Translation of the Tight Junction Protein Zona Occludens-1 Modulating Intestinal Epithelial Barrier Function

Jie Chen^*,,,, Lan Xiao^*,,, Jaladanki N. Rao^*,, Tongtong Zou^*,, Lan Liu^*,, Emily Bellavance^*,, Myriam Gorospe^||, and Jian-Ying Wang^*,,¶

*Cell Biology Group, Department of Surgery and ^¶Department of Pathology, University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201; and ^||Laboratory of Cellular and Molecular Biology, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224

Submitted February 19, 2008; Revised May 30, 2008; Accepted June 9, 2008
Monitoring Editor: William P. Tansey

The AP-1 transcription factor JunD is highly expressed in intestinal epithelial cells, but its exact role in maintaining the integrity of intestinal epithelial barrier remains unknown. The tight junction (TJ) protein zonula occludens (ZO)-1 links the intracellular domain of TJ-transmembrane proteins occludin, claudins, and junctional adhesion molecules to many cytoplasmic proteins and the actin cytoskeleton and is crucial for assembly of the TJ complex. Here, we show that JunD negatively regulates expression of ZO-1 and is implicated in the regulation of intestinal epithelial barrier function. Increased JunD levels by ectopic overexpression of the junD gene or by depleting cellular polyamines repressed ZO-1 expression and increased epithelial paracellular permeability. JunD regulated ZO-1 expression at the levels of transcription and translation. Transcriptional repression of ZO-1 by JunD was mediated through cAMP response element-binding protein-binding site within its proximal region of the ZO-1-promoter, whereas induced JunD inhibited ZO-1 mRNA translation by enhancing the interaction of the ZO-1 3'-untranslated region with RNA-binding protein T cell-restricted intracellular antigen 1-related protein. These results indicate that JunD is a biological suppressor of ZO-1 expression in intestinal epithelial cells and plays a critical role in maintaining epithelial barrier function.

These authors contributed equally to this work.

Present address: Chongqing Children's Hospital, Chongqing Medical University, Chongqing City, Chongqing 400014, China.

Address correspondence to: Jian-Ying Wang (jwang{at}smail.umaryland.edu)

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