title: Cell polarity-determining proteins Par-3 and PP-1 are involved in epithelial tight junction defects in coeliac disease.
abstract: 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.
authors.affiliation: Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité Berlin, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schumann
authors.forename: Dorothee
authors.initials: D
authors.lastname: Günzel
authors.forename: Nataly
authors.initials: N
authors.lastname: Buergel
authors.forename: Jan F
authors.initials: JF
authors.lastname: Richter
authors.forename: Hanno
authors.initials: H
authors.lastname: Troeger
authors.forename: Claudia
authors.initials: C
authors.lastname: May
authors.forename: Anja
authors.initials: A
authors.lastname: Fromm
authors.forename: Detlef
authors.initials: D
authors.lastname: Sorgenfrei
authors.forename: Severin
authors.initials: S
authors.lastname: Daum
authors.forename: Christian
authors.initials: C
authors.lastname: Bojarski
authors.forename: Martine
authors.initials: M
authors.lastname: Heyman
authors.forename: Martin
authors.initials: M
authors.lastname: Zeitz
authors.forename: Michael
authors.initials: M
authors.lastname: Fromm
authors.forename: Joerg-Dieter
authors.initials: JD
authors.lastname: Schulzke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D019921:Biotinylation; D015153:Blotting, Western; D016022:Case-Control Studies; D002446:Celiac Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018797:Cell Cycle Proteins / Q000378:metabolism* / Q000502:physiology; D016764:Cell Polarity; D057167:Claudins / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D018613:Microscopy, Confocal; D010750:Phosphoproteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D054645:Protein Phosphatase 1 / Q000378:metabolism* / Q000502:physiology; D019108:Tight Junctions / Q000737:chemistry / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D057167:Claudins; D008565:Membrane Proteins; C509689:PARD3 protein, human; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D054645:Protein Phosphatase 1