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J. Biol. Chem., Vol. 283, Issue 4, 2192-2202, January 25, 2008

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Inverse Correlation between the Extent of N-Glycan Branching and Intercellular Adhesion in Epithelia

CONTRIBUTION OF THE Na,K-ATPase β₁ SUBUNIT^*

From the Department of Physiology, School of Medicine, University of California, Los Angeles and Veterans Administration Greater Los Angeles Health Care System, Los Angeles, California 90073

The majority of cell adhesion molecules are N-glycosylated, but the role of N-glycans in intercellular adhesion in epithelia remains ill-defined. Reducing N-glycan branching of cellular glycoproteins by swainsonine, the inhibitor of N-glycan processing, tightens and stabilizes cell-cell junctions as detected by a 3-fold decrease in the paracellular permeability and a 2-3-fold increase in the resistance of the adherens junction proteins to extraction by non-ionic detergent. In addition, exposure of cells to swainsonine inhibits motility of MDCK cells. Mutagenic removal of N-glycosylation sites from the Na,K-ATPase β₁ subunit impairs cell-cell adhesion and decreases the effect of swainsonine on the paracellular permeability of the cell monolayer and also on detergent resistance of adherens junction proteins, indicating that the extent of N-glycan branching of this subunit is important for intercellular adhesion. The N-glycans of the Na,K-ATPase β₁ subunit and E-cadherin are less complex in tight renal epithelia than in the leakier intestinal epithelium. The complexity of the N-glycans linked to these proteins gradually decreases upon the formation of a tight monolayer from dispersed MDCK cells. This correlates with a cell-cell adhesion-induced increase in expression of GnT-III (stops N-glycan branching) and a decrease in expression of GnTs IVC and V (promote N-glycan branching) as detected by real-time quantitative PCR. Consistent with these results, partial silencing of the gene encoding GnT-III increases branching of N-glycans linked to the Na,K-ATPase β₁ subunit and other glycoproteins and results in a 2-fold increase in the paracellular permeability of MDCK cell monolayers. These results suggest epithelial cells can regulate tightness of cell junctions via remodeling of N-glycans, including those linked to the Na,K-ATPase β₁-subunit.

Received for publication, June 8, 2007 , and in revised form, November 14, 2007.

^* This work was supported in part by National Institutes of Health Grants DK077149, DK46917, DK58333, D53642, and the USVA. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2 and Figs. S1-S4.

¹ To whom correspondence should be addressed: VAGLAHS/West LA, Bldg. 113, Rm. 324, 11301 Wilshire Blvd, Los Angeles, CA 90073. Tel.: 310-268-4672; Fax: 310-312-9478; E-mail: olgav{at}ucla.edu.

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