Fiche publication
Date publication
mai 2016
Journal
The Journal of biological chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ANGELOT-DELETTRE Fanny
Tous les auteurs :
Martin KR, Kantari-Mimoun C, Yin M, Pederzoli-Ribeil M, Angelot-Delettre F, Ceroi A, Grauffel C, Benhamou M, Reuter N, Saas P, Frachet P, Boulanger CM, Witko-Sarsat V
Lien Pubmed
Résumé
Proteinase 3 (PR3), the autoantigen in granulomatosis with polyangiitis, is expressed at the plasma membrane of resting neutrophils, and this membrane expression increases during both activation and apoptosis. Using surface plasmon resonance and protein-lipid overlay assays, this study demonstrates that PR3 is a phosphatidylserine-binding protein and this interaction is dependent on the hydrophobic patch responsible for membrane anchorage. Molecular simulations suggest that PR3 interacts with phosphatidylserine via a small number of amino acids, which engage in long lasting interactions with the lipid heads. As phosphatidylserine is a major component of microvesicles (MVs), this study also examined the consequences of this interaction on MV production and function. PR3-expressing cells produced significantly fewer MVs during both activation and apoptosis, and this reduction was dependent on the ability of PR3 to associate with the membrane as mutating the hydrophobic patch restored MV production. Functionally, activation-evoked MVs from PR3-expressing cells induced a significantly larger respiratory burst in human neutrophils compared with control MVs. Conversely, MVs generated during apoptosis inhibited the basal respiratory burst in human neutrophils, and those generated from PR3-expressing cells hampered this inhibition. Given that membrane expression of PR3 is increased in patients with granulomatosis with polyangiitis, MVs generated from neutrophils expressing membrane PR3 may potentiate oxidative damage of endothelial cells and promote the systemic inflammation observed in this disease.
Mots clés
Animals, Apoptosis, Cell Line, Cell-Derived Microparticles, metabolism, Granulomatosis with Polyangiitis, enzymology, Humans, Male, Mice, Mice, Inbred C57BL, Molecular Docking Simulation, Myeloblastin, chemistry, Neutrophils, metabolism, Phosphatidylserines, metabolism, Phospholipid Transfer Proteins, metabolism, Rats, Respiratory Burst
Référence
J. Biol. Chem.. 2016 May;291(20):10476-89
