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

被引:145
作者
Buzza, Marguerite S. [1 ,2 ]
Netzel-Arnett, Sarah [1 ,2 ]
Shea-Donohue, Terez [3 ]
Zhao, Aiping [3 ]
Lin, Chen-Yong [4 ]
List, Karin [5 ,6 ]
Szabo, Roman [7 ]
Fasano, Alessio [3 ]
Bugge, Thomas H. [7 ]
Antalis, Toni M. [1 ,2 ]
机构
[1] Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, Baltimore, MD 21201 USA
[2] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA
[3] Univ Maryland, Sch Med, Mucosal Biol Res Ctr, Baltimore, MD 21201 USA
[4] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA
[5] Wayne State Univ, Dept Pharmacol, Detroit, MI 48201 USA
[6] Karmanos Canc Inst, Detroit, MI 48201 USA
[7] Natl Inst Dent & Cranofacial Res, Proteases & Tissue Remodeling Sect, NIH, Bethesda, MD 20892 USA
基金
美国国家卫生研究院; 英国医学研究理事会;
关键词
claudin-2; intestinal barrier; St14; type II transmembrane serine protease; tight junction; SURFACE PROTEOLYTIC-ENZYMES; INFLAMMATORY-BOWEL-DISEASE; KINASE C-ZETA; TIGHT JUNCTIONS; CELL-LINES; EXPRESSION; ACTIVATION; CLAUDIN-2; DIFFERENTIATION; INHIBITION;
D O I
10.1073/pnas.0903923107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:4200 / 4205
页数:6
相关论文
共 28 条
[1]   Ichthyosis, Follicular Atrophoderma, and Hypotrichosis Caused by Mutations in ST14 Is Associated with Impaired Profilaggrin Processing [J].
Alef, Thomas ;
Torres, Serena ;
Hausser, Ingrid ;
Metze, Dieter ;
Tuersen, Uemit ;
Lestringant, Gilles G. ;
Hennies, Hans Christian .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2009, 129 (04) :862-869
[2]   Claudin-8 expression in renal epithelial cells augments the paracellular barrier by replacing endogenous claudin-2 [J].
Angelow, Susanne ;
Schneeberger, Eveline E. ;
Yu, Alan S. L. .
JOURNAL OF MEMBRANE BIOLOGY, 2007, 215 (2-3) :147-159
[3]   Phosphorylation of claudin-4 is required for tight junction formation in a human keratinocyte cell line [J].
Aono, Shinya ;
Hirai, Yohei .
EXPERIMENTAL CELL RESEARCH, 2008, 314 (18) :3326-3339
[4]   PROTEASE INHIBITORS SUPPRESS THE FORMATION OF TIGHT JUNCTIONS IN GASTROINTESTINAL CELL-LINES [J].
BACHER, A ;
GRIEBL, K ;
MACKAMUL, S ;
MITREITER, R ;
MUCKTER, H ;
BENSHAUL, Y .
EXPERIMENTAL CELL RESEARCH, 1992, 200 (01) :97-104
[5]   Matriptase-dependent cell surface proteolysis in epithelial development and pathogenesis [J].
Bugge, Thomas H. ;
List, Karin ;
Szabo, Roman .
FRONTIERS IN BIOSCIENCE-LANDMARK, 2007, 12 :5060-5070
[6]   Cytokine regulation of tight junctions [J].
Capaldo, Christopher T. ;
Nusrat, Asma .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 2009, 1788 (04) :864-871
[7]   A differentiation-dependent splice variant of myosin light chain kinase, MLCK1, regulates epithelial tight junction permeability [J].
Clayburgh, DR ;
Rosen, S ;
Witkowski, ED ;
Wang, FJ ;
Blair, S ;
Dudek, S ;
Garcia, JGN ;
Alverdy, JC ;
Turner, JR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (53) :55506-55513
[8]   Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure [J].
El Asmar, R ;
Panigrahi, P ;
Bamford, P ;
Berti, I ;
Not, T ;
Coppa, G ;
Catassi, C ;
Fasano, A .
GASTROENTEROLOGY, 2002, 123 (05) :1607-1615
[9]   Differential expression of claudin-2 along the human intestine: Implication of GATA-4 in the maintenance of claudin-2 in differentiating cells [J].
Escaffit, F ;
Boudreau, F ;
Beaulieu, JF .
JOURNAL OF CELLULAR PHYSIOLOGY, 2005, 203 (01) :15-26
[10]  
Förbs D, 2005, INT J ONCOL, V27, P1061