Aiping M Zhao

Publication Detail

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

Marguerite S Buzza; Sarah Netzel-Arnett; Terez Shea-Donohue; Aiping Zhao; Chen-Yong Lin; Karin List; Roman Szabo; Alessio Fasano; Thomas H Bugge; Toni M Antalis (Profiled Authors: Toni Antalis; Alessio Fasano; Terez Shea-Donohue; Aiping M Zhao)

Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Proceedings of the National Academy of Sciences of the United States of America 2010;107(9):4200-5.

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 PKCzeta-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.

5 Originating Grant

• 1.

  ANTALIS, TONI M.

  Protease Pathways in the Gastrointestinal Tract

  25 July 2009 - 30 June 2011

  NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES

• 2.

  Antalis, Toni M

  New Function for the Serpin PAI-2 as a Regular of pRb

  1 August 2003 - 31 May 2009

  NATIONAL CANCER INSTITUTE

• 3.

  Antalis, Toni M

  NEW FUNCTION SERPIN PAI 2 AS A REGULAR OF RB

  1 July 2002 - 30 June 2010

  NATIONAL CANCER INSTITUTE

• 4.

  FASANO, ALESSIO

  Zot, Zonulin, and Pathophysiology of Intestinal Tight Junctions

  1 May 1996 - 31 July 2016

  NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES

• 5.

  STRICKLAND, DUDLEY K.

  Vascular Biology Training Program

  1 July 1991 - 31 August 2014

  NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

Scientific Context

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