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

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, whic...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2010-03, Vol.107 (9), p.4200-4205
Main Authors: 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
Format: Article
Language:English
Subjects:
Biological Sciences
Caco 2 cells
Calcium
Cell lines
Cell Membrane - enzymology
Cell Proliferation
Claudins
Epithelial cells
Gene expression regulation
Gene Silencing
Humans
Intestinal Mucosa - metabolism
Large intestine
Membrane Proteins - metabolism
Membranes
Messenger RNA
Permeability
Physiological regulation
Proteases
Protein Kinase C - metabolism
Proteins
Ribonucleic acid
RNA
RNA, Small Interfering
Rodents
Serine Endopeptidases - genetics
Serine Endopeptidases - metabolism
Signal Transduction
Small interfering RNA
Small intestine
Tight junctions
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Summary: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 PKCĪ¶-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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0903923107