title: Interaction of proteinase 3 with its associated partners: implications in the pathogenesis of Wegener's granulomatosis.
abstract: OBJECTIVE
  This review focuses on proteinase 3 (PR3), the preferred target of antineutrophil cytoplasmic antibodies (ANCAs) in Wegener's granulomatosis. Deciphering the molecular associations that PR3 can make with its cognate partners might help to understand its pathophysiological significance in Wegener's granulomatosis and the potential role of ANCA as modulator of PR3 functions.
  
  
  RESULTS
  In neutrophils, PR3 is mainly localized within azurophilic granules but is also detected at the plasma membrane. Among PR3 partners (CD16, CD11b/CD18), CD177, a glycosylphosphatidylinositol (GPI)-anchored membrane protein is a potential receptor for PR3. In addition, PR3 can be externalized at the plasma membrane at a very early stage of neutrophil apoptosis, in the absence of degranulation. In these conditions, PR3 is associated with specific partners including phospholipidscramblase-1 and calreticulin. Interestingly, apoptosis-induced PR3 membrane expression significantly impaired macrophage phagocytosis. This new role of PR3 acting as a 'don't eat me signal' that delays neutrophil clearance might potentiate inflammation and autoimmunity.
  
  
  CONCLUSIONS
  Since PR3 membrane expression seems to represent a key element in the inflammatory and autoimmunity process, elucidation of the molecular basis of PR3 interaction with the plasma membrane or with receptor proteins led to the possibility of targeted therapy.
authors.affiliation: Inserm U567 and Université Paris Descartes, Cochin Hospital, Paris, France. veronique.witko@inserm.fr
authors.forename: Véronique
authors.initials: V
authors.lastname: Witko-Sarsat
authors.forename: Nathalie
authors.initials: N
authors.lastname: Reuter
authors.forename: Luc
authors.initials: L
authors.lastname: Mouthon
mesh_terms: D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000378:metabolism*; D017209:Apoptosis / Q000276:immunology; D015551:Autoimmunity / Q000502:physiology*; D058851:GPI-Linked Proteins; D014890:Granulomatosis with Polyangiitis / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D007519:Isoantigens / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D053146:Myeloblastin / Q000737:chemistry / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D011956:Receptors, Cell Surface / Q000378:metabolism
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; C407242:CD177 protein, human; D058851:GPI-Linked Proteins; D007519:Isoantigens; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D053146:Myeloblastin