Cleavage of the Human C5A Receptor by Protienases Derived from Porphyromonas Gingivalis

Jagels, Mark A.; Ember, Julia A.; Travis, James; Potempa, Jan; Pike, Robert N.; Hugli, Tony E.

doi:10.1007/978-1-4613-0335-0_19

Cited by 77 publications

(67 citation statements)

References 10 publications

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“…In addition, OM compartmentalization could be coupled to LPS and/or OM protein translocation processes (44). It has been shown that OMV produced by P. gingivalis have proteolytic activity, mainly because of the presence of gingipains (34) and that this enables the degradation of host proteins, including collagen, elements of the complement cascade, and cell receptors (45,46). Furthermore, P. gingivalis OMV can be internalized and subsequently digest cell components resulting in cellular malfunction (12).…”

Section: Discussionmentioning

confidence: 99%

Selective Sorting of Cargo Proteins into Bacterial Membrane Vesicles

Haurat¹,

Aduse‐Opoku

Rangarajan

et al. 2011

Journal of Biological Chemistry

269

290

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In contrast to the well established multiple cellular roles of membrane vesicles in eukaryotic cell biology, outer membrane vesicles (OMV) produced via blebbing of prokaryotic membranes have frequently been regarded as cell debris or microscopy artifacts. Increasingly, however, bacterial membrane vesicles are thought to play a role in microbial virulence, although it remains to be determined whether OMV result from a directed process or from passive disintegration of the outer membrane. Here we establish that the human oral pathogen Porphyromonas gingivalis has a mechanism to selectively sort proteins into OMV, resulting in the preferential packaging of virulence factors into OMV and the exclusion of abundant outer membrane proteins from the protein cargo. Furthermore, we show a critical role for lipopolysaccharide in directing this sorting mechanism. The existence of a process to package specific virulence factors into OMV may significantly alter our current understanding of host-pathogen interactions.

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Section: Discussionmentioning

confidence: 99%

Selective Sorting of Cargo Proteins into Bacterial Membrane Vesicles

Haurat¹,

Aduse‐Opoku

Rangarajan

et al. 2011

Journal of Biological Chemistry

269

290

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“…Bordetella pertussis, for example, produces pertussis toxin that inhibits GPCRs by ADP-ribosylation of the G protein (17) and Porphyromonas gingivalis produces a proteinase, which cleaves the C5aR (18). Furthermore, different cell wall components of Cryptococcus neoformans are described to inhibit neutrophil chemotaxis toward IL-8, fMLP, and C5a (19,20), whereas endotoxins of Gram-negative bacteria down-regulate CXC and CC chemokine receptor expression (21,22).…”

Section: Discussionmentioning

confidence: 99%

Chemotaxis Inhibitory Protein of Staphylococcus aureus Binds Specifically to the C5a and Formylated Peptide Receptor

Postma

Poppelier

Galen

et al. 2004

The Journal of Immunology

199

148

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Chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) is an exoprotein produced by several strains of S. aureus, and a potent inhibitor of neutrophil and monocyte chemotaxis toward C5a and formylated peptides like fMLP. These chemoattractants act on their target cells by binding and activating the C5aR and formylated peptide receptor (FPR), respectively. In the present report, we examined the mechanism by which CHIPS affects both of these receptors. We showed that CHIPS blocked binding of anti-C5aR mAb and formylated peptide to human neutrophils as efficiently at temperatures of 0 and 37°C, implying that it is independent of signal transducing systems. This was confirmed by showing that CHIPS acts completely independently of ATP. Additionally, CHIPS was not internalized upon binding to neutrophils. Furthermore, we showed that CHIPS binds specifically to the C5aR and FPR expressed on U937 cells. This binding was functional in blocking C5a- and fMLP-induced calcium mobilization in these cell lines. These results suggest that CHIPS binds directly to the C5aR and FPR, thereby preventing the natural ligands from activating these receptors. The apparent Kd values of CHIPS for the C5aR and FPR were 1.1 ± 0.2 nM and 35.4 ± 7.7 nM, respectively. Moreover, after screening a wide variety of other G protein-coupled receptors, CHIPS was found to affect exclusively the C5aR and FPR. This selectivity and high-affinity binding with potent antagonistic effects makes CHIPS a promising lead for the development of new anti-inflammatory compounds for diseases in which damage by neutrophils plays a key role.

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“…Cysteine proteinases of the protozoan Entamoeba histolytica (26) and the major periodontal disease causative agent Porphyromonas gingivalis (27) have been shown to degrade C5a and the receptor, respectively. To address this issue, we investigated the effect of ASP on C5a receptor or C5a.…”

Section: Effect Of Asp On Neutrophil C5a-receptor and C5amentioning

confidence: 99%

Production of C5a by ASP, a Serine Protease Released from Aeromonas sobria

Nitta¹,

Imamura²,

Wada

et al. 2008

The Journal of Immunology

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Aeromonas sobria causes pus and edema at sites of infection. However, the mechanisms underlying these effects have not been elucidated. C5a, the amino-terminal fragment of the complement 5th component (C5), mimics these events. To investigate the involvement of C5a in the pathophysiology of A. sobria infection, we examined release of C5a from human C5 by a serine protease (ASP), a putative virulence factor secreted by this bacterium. C5 incubated with enzymatically active ASP induced neutrophil migration in a dose-dependent manner from an ASP concentration of 3 nM and in an incubation time-dependent manner in as little as 7 min, with neutrophil accumulation in guinea pigs at intradermal injection sites and neutrophil superoxide release. These effects on neutrophils were inhibited by a C5a-receptor antagonist. The ASP incubation mixture with C5 but not C3 elicited vascular leakage in a dose- and incubation time-dependent manner, which was inhibited by a histamine H1-receptor antagonist. Together with these C5a-like activities, ASP cleaved C5 to release only one C5a Ag, the m.w. of which was similar to that of C5a. Immunoblotting using an anti-C5a Ab revealed generation of a C5a-like fragment from human plasma incubated with ASP. These results suggest that ASP-elicited neutrophil migration and vascular leakage via C5a production from C5 could occur in vivo, which was supported by that ASP did not affect functions of C5a and neutrophil C5a receptor. Through C5a generation, ASP could be associated with the induction of pus and edema caused by infection with this bacterium.

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Cleavage of the Human C5A Receptor by Protienases Derived from Porphyromonas Gingivalis

Cited by 77 publications

References 10 publications

Selective Sorting of Cargo Proteins into Bacterial Membrane Vesicles

Selective Sorting of Cargo Proteins into Bacterial Membrane Vesicles

Chemotaxis Inhibitory Protein of Staphylococcus aureus Binds Specifically to the C5a and Formylated Peptide Receptor

Production of C5a by ASP, a Serine Protease Released from Aeromonas sobria

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