Aiping M Zhao

Publication Detail

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Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2.

Amit Tripathi; Karen M Lammers; Simeon Goldblum; Terez Shea-Donohue; Sarah Netzel-Arnett; Marguerite S Buzza; Toni M Antalis; Stefanie N Vogel; Aiping Zhao; Shiqi Yang; et al. (Profiled Authors: Toni Antalis; Alessio Fasano; Simeon E Goldblum; Terez Shea-Donohue; Stefanie N Vogel; Aiping M Zhao; Karen Lammers)

Mucosal Biology Research Center, Center for Vascular and Inflammatory Diseases and Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 20201, USA.
Proceedings of the National Academy of Sciences of the United States of America 2009;106(39):16799-804.

Increased intestinal permeability (IP) has emerged recently as a common underlying mechanism in the pathogenesis of allergic, inflammatory, and autoimmune diseases. The characterization of zonulin, the only physiological mediator known to regulate IP reversibly, has remained elusive. Through proteomic analysis of human sera, we have now identified human zonulin as the precursor for haptoglobin-2 (pre-HP2). Although mature HP is known to scavenge free hemoglobin (Hb) to inhibit its oxidative activity, no function has ever been ascribed to its uncleaved precursor form. We found that the single-chain zonulin contains an EGF-like motif that leads to transactivation of EGF receptor (EGFR) via proteinase-activated receptor 2 (PAR(2)) activation. Activation of these 2 receptors was coupled to increased IP. The siRNA-induced silencing of PAR(2) or the use of PAR(2)(-/-) mice prevented loss of barrier integrity. Proteolytic cleavage of zonulin into its alpha(2)- and beta-subunits neutralized its ability to both activate EGFR and increase IP. Quantitative gene expression revealed that zonulin is overexpressed in the intestinal mucosa of subjects with celiac disease. To our knowledge, this is the initial example of a molecule that exerts a biological activity in its precursor form that is distinct from the function of its mature form. Our results therefore characterize zonulin as a previously undescribed ligand that engages a key signalosome involved in the pathogenesis of human immune-mediated diseases that can be targeted for therapeutic interventions.

6 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.

  Vogel, Stefanie N

  DIFFERENTIATIVE SIGNALS FOR MACROPHAGE ACTIVATION

  1 April 1982 - 31 March 2010

  NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES

• 6.

  VOGEL, STEFANIE N.

  Differentiative Signals for Macrophage Activation

  1 April 1982 - 31 March 2015

  NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES

Scientific Context

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