MUC13 negatively regulates tight junction proteins and intestinal epithelial barrier integrity via Protein Kinase C.

Glycosylated mucin proteins contribute- to the essential barrier function of the intestinal epithelium. The transmembrane mucin MUC13 is an abundant intestinal glycoprotein with important functions for mucosal maintenance that are not yet completely understood. We demonstrate that in intestinal epithelial monolayers MUC13 localized to both the apical surface and the tight junction (TJ) region on the lateral membrane. MUC13 deletion resulted in increased transepithelial resistance (TEER) and reduced translocation of small solutes. TEER build up in ▵MUC13 cells could be prevented by addition of MLCK, ROCK or PKC inhibitors. TJ proteins including claudins and occludin were highly increased in membrane fractions of MUC13 knockout cells. Removal of the MUC13 cytoplasmic tail (CT) also altered TJ composition but did not affect TEER. The increased buildup of TJ complexes in ▵MUC13 and MUC13-▵CT cells was dependent on PKC. The responsible PKC member might be PKCδ based on elevated protein levels in the absence of full-length MUC13. Our results demonstrate for the first time that a mucin protein can negatively regulate tight junction function and stimulate intestinal barrier permeability.