Membrane proteinase 3 and its interactions within microdomains of neutrophil membranes

Fridlich, Ram; David, Alina; Aviram, Irit

doi:10.1002/jcb.20901

Cited by 21 publications

(21 citation statements)

References 34 publications

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“…studies, however, suggest that PR3 has a greater role than NE in IL-1β processing and secretion. (3) PR3 is localized in the same lipid raft domains (75,76) as A1AT (5,20) and LA (77). Bilayer-bound PR3 has a reduced catalytic efficiency, whereas its inhibition by A1AT is more important than that observed for the soluble form of the enzyme.…”

Section: Resultsmentioning

confidence: 99%

α-Linoleic Acid Enhances the Capacity of α1-Antitrypsin to Inhibit Lipopolysaccharide-Induced IL-1β in Human Blood Neutrophils

Aggarwal

Korenbaum

Mahadeva

et al. 2016

Mol Med

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Section: Resultsmentioning

confidence: 99%

α-Linoleic Acid Enhances the Capacity of α1-Antitrypsin to Inhibit Lipopolysaccharide-Induced IL-1β in Human Blood Neutrophils

Aggarwal

Korenbaum

Mahadeva

et al. 2016

Mol Med

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“…An association of PR3 with membrane lipid rafts and potential interactions of PR3 with the ␤ 2 -integrins CD18 and CD11b and the Fc␥RIIIb receptor has been reported some time ago (7,8). PR3 was also associated with a myristoylated membrane protein with a translocase activity, phospholipid scramblase 1, present in lipid rafts (9).…”

Section: Proteinase 3 (Pr3)mentioning

confidence: 86%

A Hydrophobic Patch on Proteinase 3, the Target of Autoantibodies in Wegener Granulomatosis, Mediates Membrane Binding via NB1 Receptors

Korkmaz

Kuhl

Bayat

et al. 2008

Journal of Biological Chemistry

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Proteinase 3 (PR3), the target antigen of antineutrophil cytoplasm autoantibodies, which are found in patients with Wegener granulomatosis, is a neutrophil serine protease localized within cytoplasmic granules. Recently, the human neutrophil antigen NB1 was identified as a specific neutrophil cell surface receptor of PR3. We hypothesized that the unique hydrophobic cluster of PR3 that is not present on human neutrophil elastase and cathepsin G and presumably is also missing in other human PR3 homologs accounts for its binding to the NB1 receptor expressed on the cellular surface of NB1 cells. Instead of generating and testing various artificial human PR3 mutants, we cloned and expressed the very closely related gibbon (Hylobates pileatus) PR3 homolog, which did not bind to the human NB1 receptor. Moreover, a human-gibbon hybrid constructed from the N-and C-terminal half of the human and gibbon PR3, respectively, also did not interact with human NB1. The C-terminal half of gibbon PR3 differs only by 9 residues from human PR3, among which four closely spaced hydrophobic residues are substituted in a nonconservative manner (F166L, W218R, G219A, and L223H). The NB1-bound PR3 was active and was cleared from the surface by ␣-1-protease inhibitor. Conformational distortion of the hydrophobic 217-225 loop by ␣-1-protease inhibitor most likely triggers rapid solubilization.

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“…In that respect, the previously described localization of PR3 in membrane rafts, together with ␤2 integrins and Fc␥R, is worth noting. 40,41 Recent data have suggested that PR3 membrane expression would result from mPR3 close association with CD177. 30,31 We confirm that CD177, exclusively present on the mPR3 ϩ neutrophil subset, is upregulated as mPR3 by TNF-␣ activation without adhesion.…”

Section: Discussionmentioning

confidence: 99%

Increased Membrane Expression of Proteinase 3 during Neutrophil Adhesion in the Presence of Anti–Proteinase 3 Antibodies

Brachemi¹,

Mambole²,

Fakhouri³

et al. 2007

Journal of the American Society of Nephrology

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We investigated membrane proteinase 3 (mPR3) expression during TNF-␣-induced adhesion of neutrophils in the presence of anti-PR3 antibodies, a situation occurring during anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis. Three increasing levels of mPR3 expression were observed on the mPR3 ϩ neutrophil subset after stepwise cell activation. TNF-␣ activation without adhesion, TNF-␣-induced adhesion, and adhesion in the presence of anti-PR3 mAb or human anti-PR3 ANCA resulted, respectively, in a two-, seven-, and 24-fold increase of mPR3 levels. In plasma, anti-PR3 antibodies poorly recognized suspended neutrophils, whereas they bound to mPR3 on adherent cells. mPR3 upregulation was also triggered by IL-8, formyl-methionyl-leucyl-phenylalanine (fMLP), and neutrophil adhesion to activated human umbilical vein endothelial cells. It involved ␤2 integrins and Fc␥ receptor, because it was prevented by anti-CD18 antibodies and was not observed with anti-PR3 F(abЈ) 2 . Furthermore, it was specific to anti-PR3 mAb, and no mPR3 upregulation was observed with antimyeloperoxidase or anti-HLA-ABC mAb. Newly expressed mPR3 molecules, after TNF-induced adhesion, were mobilized from secretory vesicles (CD35 ϩ ) and secondary granules (CD11b ϩ ). The adhesionand antibody-dependent upregulations of mPR3 expression occurred with little azurophilic granule degranulation, no sign of apoptosis, and no further CD177 upregulation. In conclusion, this study describes an amplifying loop in polymorphonuclear neutrophil activation process, whereby ANCA are involved in the membrane expression of their own antigen during cell adhesion. This could explain the restriction of ANCA-associated vasculitis to small vessels, the main site of neutrophil adhesion.

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Membrane proteinase 3 and its interactions within microdomains of neutrophil membranes

Cited by 21 publications

References 34 publications

α-Linoleic Acid Enhances the Capacity of α1-Antitrypsin to Inhibit Lipopolysaccharide-Induced IL-1β in Human Blood Neutrophils

α-Linoleic Acid Enhances the Capacity of α1-Antitrypsin to Inhibit Lipopolysaccharide-Induced IL-1β in Human Blood Neutrophils

A Hydrophobic Patch on Proteinase 3, the Target of Autoantibodies in Wegener Granulomatosis, Mediates Membrane Binding via NB1 Receptors

Increased Membrane Expression of Proteinase 3 during Neutrophil Adhesion in the Presence of Anti–Proteinase 3 Antibodies

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