Membrane-anchored serine protease matriptase regulates epithelial barrier formation and permeability in the intestine

作者：Buzza Marguerite S; Netzel Arnett Sarah; Shea Donohue Terez; Zhao Aiping; Lin Chen Yong; List Karin; Szabo Roman; Fasano Alessio; Bugge Thomas H; Antalis Toni M^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2010, 107(9): 4200-4205.

DOI：10.1073/pnas.0903923107

• claudin-2
• intestinal barrier
• St14
• type II transmembrane serine protease
• tight junction

The intestinal epithelium serves as a major protective barrier between the mammalian host and the external environment. Here we show that the transmembrane serine protease matriptase plays a pivotol role in the formation and integrity of the intestinal epithelial barrier. St14 hypomorphic mice, which have a 100-fold reduction in intestinal matriptase mRNA levels, display a 35% reduction in intestinal transepithelial electrical resistance (TEER). Matriptase is expressed during intestinal epithelial differentiation and colocalizes with E-cadherin to apical junctional complexes (AJC) in differentiated polarized Caco-2 monolayers. Inhibition of matriptase activity using a specific peptide inhibitor or by knockdown of matriptase by siRNA disrupts the development of TEER in barrier-forming Caco-2 monolayers and increases paracellular permeability to macromolecular FITC-dextran. Loss of matriptase was associated with enhanced expression and incorporation of the permeability associated, "leaky" tight junction protein claudin-2 at intercellular junctions. Knockdown of claudin-2 enhanced the development of TEER in matriptase-silenced Caco-2 monolayers, suggesting that the reduced barrier integrity was caused, at least in part, by an inability to regulate claudin-2 expression and incorporation into junctions. We find that matriptase enhances the rate of claudin-2 protein turnover, and that this is mediated indirectly through an atypical PKC zeta-dependent signaling pathway. These results support a key role for matriptase in regulating intestinal epithelial barrier competence, and suggest an intriguing link between pericellular serine protease activity and tight junction assembly in polarized epithelia.

• 出版日期2010-3-2