Cell polarity-determining proteins Par-3 and PP-1 are involved in epithelial tight junction defects in coeliac disease

Gut. 2012 Feb;61(2):220-8. doi: 10.1136/gutjnl-2011-300123. Epub 2011 Aug 24.


Background: Epithelial barrier defects are well known in coeliac disease, but the mechanisms are only poorly defined. It is unclear, whether barrier disturbance reflects upregulated epithelial transcytosis or paracellular leakage.

Objective: To characterise the molecular structure and function of the epithelial tight junction (TJ) and mechanisms of its dysregulation.

Methods: Molecular analysis of proteins involved in TJ assembly and their regulation was performed by western blotting and confocal microscopy correlated to electrophysiology.

Results: A complex alteration of the composition of epithelial TJ proteins (with more pore-forming claudins like claudin-2 and a reduction in tightening claudins like claudin-3, -5 and -7) was found for protein expression and subcellular localisation, responsible for an increase in paracellular biotin-NHS uptake. In contrast, epithelial apoptosis was only moderately elevated (accounting for a minor portion of barrier defects) and epithelial gross lesions--for example, at cell extrusion zones, were absent. This TJ alteration was linked to an altered localisation/expression of proteins regulating TJ assembly, the polarity complex protein Par-3 and the serine-/threonine phosphatase PP-1.

Conclusions: Changes in cell polarity proteins Par-3 and PP-1 are associated with altered expression and assembly of TJ proteins claudin-2, -3, -5 and -7 and ZO-1, causing paracellular leakage in active coeliac disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Apoptosis
  • Biotinylation
  • Blotting, Western
  • Case-Control Studies
  • Celiac Disease / metabolism*
  • Celiac Disease / pathology
  • Celiac Disease / physiopathology
  • Cell Cycle Proteins / metabolism*
  • Cell Cycle Proteins / physiology
  • Cell Polarity*
  • Claudins / metabolism
  • Humans
  • Intestinal Mucosa / chemistry
  • Intestinal Mucosa / metabolism*
  • Membrane Proteins / metabolism*
  • Membrane Proteins / physiology
  • Microscopy, Confocal
  • Phosphoproteins / metabolism
  • Polymerase Chain Reaction
  • Protein Phosphatase 1 / metabolism*
  • Protein Phosphatase 1 / physiology
  • Tight Junctions / chemistry
  • Tight Junctions / metabolism*
  • Zonula Occludens-1 Protein


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Claudins
  • Membrane Proteins
  • PARD3 protein, human
  • Phosphoproteins
  • TJP1 protein, human
  • Zonula Occludens-1 Protein
  • Protein Phosphatase 1