Proteolytic activity-independent activation of the immune response by gingipains from Porphyromonas gingivalis

2022
journal article
article
dc.abstract.enPorphyromonas gingivalis, a keystone pathogen in periodontitis (PD), produces cysteine proteases named gingipains (RgpA, RgpB, and Kgp), which strongly affect the host immune system. The range of action of gingipains is extended by their release as components of outer membrane vesicles, which efficiently diffuse into surrounding gingival tissues. However, away from the anaerobic environment of periodontal pockets, increased oxygen levels lead to oxidation of the catalytic cysteine residues of gingipains, inactivating their proteolytic activity. In this context, the influence of catalytically inactive gingipains on periodontal tissues is of significant interest. Here, we show that proteolytically inactive RgpA induced a proinflammatory response in both gingival keratinocytes and dendritic cells. Inactive RgpA is bound to the cell surface of gingival keratinocytes in the region of lipid rafts, and using affinity chromatography, we identified RgpA-interacting proteins, including epidermal growth factor receptor (EGFR). Next, we showed that EGFR interaction with inactive RgpA stimulated the expression of inflammatory cytokines. The response was mediated via the EGFR–phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway, which when activated in the gingival tissue rich in dendritic cells in the proximity of the alveolar bone, may significantly contribute to bone resorption and the progress of PD. Taken together, these findings broaden our understanding of the biological role of gingipains, which in acting as proinflammatory factors in the gingival tissue, create a favorable milieu for the growth of inflammophilic pathobionts. IMPORTANCE: Gingipain cysteine proteases are essential virulence factors of Porphyromonas gingivalis, an oral bacterium implicated in development of periodontitis. Gingipains diffusing from anaerobic periodontal pockets lose proteolytic activity in the oxygenated environment of gingival tissues. We found that despite the loss of activity, gingipains still elicit a strong inflammatory response, which may contribute to the progression of periodontitis and bone resorption. Moreover, we identified the host molecules utilized by the pathogen as receptors for proteolytically inactivated gingipains. The broad distribution of those receptors in human tissue suggests their involvement in systemic diseases associated with periodontal pathogens.pl
dc.affiliationWydział Biochemii, Biofizyki i Biotechnologii : Zakład Mikrobiologiipl
dc.affiliationWydział Biochemii, Biofizyki i Biotechnologii : Zakład Biochemii Porównawczej i Bioanalitykipl
dc.contributor.authorCiastoń, Izabela - 163063 pl
dc.contributor.authorBudziaszek, Joanna - 229938 pl
dc.contributor.authorSatała, Dorota - 177568 pl
dc.contributor.authorPotempa, Barbarapl
dc.contributor.authorFuchs, Andrewpl
dc.contributor.authorRąpała-Kozik, Maria - 131641 pl
dc.contributor.authorMizgalska, Danuta - 147955 pl
dc.contributor.authorDobosz, Ewelina - 152045 pl
dc.contributor.authorLamont, Richard J.pl
dc.contributor.authorPotempa, Jan - 131531 pl
dc.contributor.authorKozieł, Joanna - 129350 pl
dc.date.accessioned2022-11-16T07:48:42Z
dc.date.available2022-11-16T07:48:42Z
dc.date.issued2022pl
dc.date.openaccess0
dc.description.accesstimew momencie opublikowania
dc.description.additionalBibliogr.pl
dc.description.number3pl
dc.description.versionostateczna wersja wydawcy
dc.description.volume13pl
dc.identifier.articleide03787-21pl
dc.identifier.doi10.1128/mbio.03787-21pl
dc.identifier.eissn2150-7511pl
dc.identifier.issn2161-2129pl
dc.identifier.urihttps://ruj.uj.edu.pl/xmlui/handle/item/303712
dc.languageengpl
dc.language.containerengpl
dc.rightsUdzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa*
dc.rights.licenceCC-BY
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/legalcode.pl*
dc.share.typeotwarte czasopismo
dc.subject.enPorphyromonas gingivalispl
dc.subject.engingipainspl
dc.subject.eninflammationpl
dc.subject.enperiodontitispl
dc.subject.enepidermal growth factor receptor (EGFR)pl
dc.subtypeArticlepl
dc.titleProteolytic activity-independent activation of the immune response by gingipains from Porphyromonas gingivalispl
dc.title.journalMBiopl
dc.typeJournalArticlepl
dspace.entity.typePublication
dc.abstract.enpl
Porphyromonas gingivalis, a keystone pathogen in periodontitis (PD), produces cysteine proteases named gingipains (RgpA, RgpB, and Kgp), which strongly affect the host immune system. The range of action of gingipains is extended by their release as components of outer membrane vesicles, which efficiently diffuse into surrounding gingival tissues. However, away from the anaerobic environment of periodontal pockets, increased oxygen levels lead to oxidation of the catalytic cysteine residues of gingipains, inactivating their proteolytic activity. In this context, the influence of catalytically inactive gingipains on periodontal tissues is of significant interest. Here, we show that proteolytically inactive RgpA induced a proinflammatory response in both gingival keratinocytes and dendritic cells. Inactive RgpA is bound to the cell surface of gingival keratinocytes in the region of lipid rafts, and using affinity chromatography, we identified RgpA-interacting proteins, including epidermal growth factor receptor (EGFR). Next, we showed that EGFR interaction with inactive RgpA stimulated the expression of inflammatory cytokines. The response was mediated via the EGFR–phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway, which when activated in the gingival tissue rich in dendritic cells in the proximity of the alveolar bone, may significantly contribute to bone resorption and the progress of PD. Taken together, these findings broaden our understanding of the biological role of gingipains, which in acting as proinflammatory factors in the gingival tissue, create a favorable milieu for the growth of inflammophilic pathobionts. IMPORTANCE: Gingipain cysteine proteases are essential virulence factors of Porphyromonas gingivalis, an oral bacterium implicated in development of periodontitis. Gingipains diffusing from anaerobic periodontal pockets lose proteolytic activity in the oxygenated environment of gingival tissues. We found that despite the loss of activity, gingipains still elicit a strong inflammatory response, which may contribute to the progression of periodontitis and bone resorption. Moreover, we identified the host molecules utilized by the pathogen as receptors for proteolytically inactivated gingipains. The broad distribution of those receptors in human tissue suggests their involvement in systemic diseases associated with periodontal pathogens.
dc.affiliationpl
Wydział Biochemii, Biofizyki i Biotechnologii : Zakład Mikrobiologii
dc.affiliationpl
Wydział Biochemii, Biofizyki i Biotechnologii : Zakład Biochemii Porównawczej i Bioanalityki
dc.contributor.authorpl
Ciastoń, Izabela - 163063
dc.contributor.authorpl
Budziaszek, Joanna - 229938
dc.contributor.authorpl
Satała, Dorota - 177568
dc.contributor.authorpl
Potempa, Barbara
dc.contributor.authorpl
Fuchs, Andrew
dc.contributor.authorpl
Rąpała-Kozik, Maria - 131641
dc.contributor.authorpl
Mizgalska, Danuta - 147955
dc.contributor.authorpl
Dobosz, Ewelina - 152045
dc.contributor.authorpl
Lamont, Richard J.
dc.contributor.authorpl
Potempa, Jan - 131531
dc.contributor.authorpl
Kozieł, Joanna - 129350
dc.date.accessioned
2022-11-16T07:48:42Z
dc.date.available
2022-11-16T07:48:42Z
dc.date.issuedpl
2022
dc.date.openaccess
0
dc.description.accesstime
w momencie opublikowania
dc.description.additionalpl
Bibliogr.
dc.description.numberpl
3
dc.description.version
ostateczna wersja wydawcy
dc.description.volumepl
13
dc.identifier.articleidpl
e03787-21
dc.identifier.doipl
10.1128/mbio.03787-21
dc.identifier.eissnpl
2150-7511
dc.identifier.issnpl
2161-2129
dc.identifier.uri
https://ruj.uj.edu.pl/xmlui/handle/item/303712
dc.languagepl
eng
dc.language.containerpl
eng
dc.rights*
Udzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa
dc.rights.licence
CC-BY
dc.rights.uri*
http://creativecommons.org/licenses/by/4.0/legalcode.pl
dc.share.type
otwarte czasopismo
dc.subject.enpl
Porphyromonas gingivalis
dc.subject.enpl
gingipains
dc.subject.enpl
inflammation
dc.subject.enpl
periodontitis
dc.subject.enpl
epidermal growth factor receptor (EGFR)
dc.subtypepl
Article
dc.titlepl
Proteolytic activity-independent activation of the immune response by gingipains from Porphyromonas gingivalis
dc.title.journalpl
MBio
dc.typepl
JournalArticle
dspace.entity.type
Publication

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