| Cleavage of the human C5A receptor by proteinases derived from Porphyromonas gingivalis: cleavage of leukocyte C5a receptor. | |
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MedLine Citation:
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PMID: 8861006 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The anaerobic bacteria P. gingivalis has been implicated as a primary causative agent in adult periodontitis. Several proteinases are produced by this bacteria and it is suggested that they contribute to virulence and to local tissue injury resulting from infection by P. gingivalis. Collagenases and cysteine proteinases (i.e., the gingipains) have been characterized as the predominant vesicular enzymes produced by this bacterium. It has been shown that an arginine-specific cysteine proteinase from P. gingivalis, called gingipain-1 or Arg-gingipain, can selectively cleave complement components C3 and C5. In the case of C5, cleavage by Arg-gingipain results in the generation of C5a, a potent chemotactic factor for PMNs. Since these bacterial proteinases are capable of generating pro-inflammatory factors at sites of infection, we examined the possibility that gingipains or other proteinases from this bacterium might attack or destroy cell surface proteins, such as receptor molecules. Using an affinity-purified rabbit antibody raised against residues 9-29 of the C5a receptor (i.e., C5aR; CD88), the signal transmitting element for the pro-inflammatory mediator C5a, we demonstrated that the mixture of proteinases in P. gingivalis vesicles cleaves the C5a receptor on human neutrophils. This vesicular proteinase activity did not require cysteine activation which indicates that proteinases other than the gingipains may be responsible for cleavage of the C5aR molecule. in addition, the purified Lys-gingipain, but not Arg-gingipain, also cleaved C5aR on the human neutrophils. The N-terminal region of CaR (residues 9-29, PDYGHYDDKDTLDLNTPVDKT) was readily cleaved by chymotrypsin, but not by trypsin, despite the presence of potential trypsin (i.e., lysyl-X) cleavage sites. The specific sites of C5aR 9-29 peptide cleavage were determined by mass spectroscopy for both chymotrypsin and Lys-gingipain. These studies suggest that the proteolytic activity in the bacterial vesicles that is responsible for cleaving C5aR is primarily a non-tryptic proteinase, distance from either Arg- or Lys-gingipain. Consequently, there appear to be additional proteinase(s) in the vesicles that attacks the cell surface molecule C5aR which are not the same (i.e., Arg- and Lys-gingipain) as were shown to generate pro-inflammatory activity from complement components C3 and C5. Evidence that the proteinases which attack the inflammatory precursor molecules (i.e., C3 and C5) exhibit different specificities than those that attack receptors to these bioactive complement products makes a particularly interesting story of how this bacteria avoids major host defense mechanisms. It is well known that generation of pro-inflammatory factors such as C3a and C5a at extra-vascular sites can promote edema, leukocyte recruitment and cellular activation responses that could lead to the release of toxic oxygen products and to phagocytosis of the bacteria. Destruction of receptors to these cellular activating factors generated by bacterial proteinases may eliminate the ability of these (i.e., complement-derived) and other mediators to carry out their anti-bacterial actions and thereby limit the host's defense mechanisms in responses to the infecting bacteria. The concept of anti-bacterial responses (i.e., oxygen radical generation and phagocytosis) being effectively eliminated at the injury site, by bacterial proteinases acting at the cellular receptor level, has not been studied in detail. In this case, the situation is particularly unusual because, once the bacterial gingipains generate potent plasma-derived inflammatory factors that can enhance edema and deliver essential nutrients to the bactgeria, other bacterial proteinases may destsroy their cellular receptors. These receptors transmit the signal activation mechanisms in the infiltrating cells that elicit bacterial killing.(ABSTRACT TRUNCATED) |
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Authors:
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M A Jagels; J A Ember; J Travis; J Potempa; R Pike; T E Hugli |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Advances in experimental medicine and biology Volume: 389 ISSN: 0065-2598 ISO Abbreviation: Adv. Exp. Med. Biol. Publication Date: 1996 |
Date Detail:
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Created Date: 1997-03-06 Completed Date: 1997-03-06 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0121103 Medline TA: Adv Exp Med Biol Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 155-64 Citation Subset: IM |
Affiliation:
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Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adhesins, Bacterial Amino Acid Sequence Antigens, CD / blood* Complement C5a* Cysteine Endopeptidases / blood*, isolation & purification Endopeptidases / blood*, isolation & purification Hemagglutinins / blood*, isolation & purification Humans Leukocytes / metabolism* Molecular Sequence Data Porphyromonas gingivalis / enzymology* Receptor, Anaphylatoxin C5a Receptors, Complement / blood* Signal Transduction / physiology |
| Grant Support | |
ID/Acronym/Agency:
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AI 17354/AI/NIAID NIH HHS; HL26148/HL/NHLBI NIH HHS; HL37090/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Adhesins, Bacterial; 0/Antigens, CD; 0/Hemagglutinins; 0/Receptor, Anaphylatoxin C5a; 0/Receptors, Complement; 80295-54-1/Complement C5a; EC 3.4.-/Endopeptidases; EC 3.4.22.-/Cysteine Endopeptidases; EC 3.4.22.37/argingipain, Porphyromonas gingivalis |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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