Dropping anchor: attachment of peptidylarginine deiminase via A-LPS to secreted outer membrane vesicles of Porphyromonas gingivalis

Gabarrini, Giorgio; Heida, Rick; Ieperen, N. van; Curtis, Michael A.; Winkelhoff, A.J. van; Dijl, Jan Maarten van

doi:10.1038/s41598-018-27223-5

Cited by 26 publications

(17 citation statements)

References 35 publications

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“…The proteomic and LPS contents of P. gingivalis OMVs have been shown to be different from those of the outer membrane by having (i) elevated levels of proteins secreted by the type IX secretion system (T9SS), which include gingipain proteases and other virulence factors, and (ii) an increased proportion of anionic A-LPS relative to neutral O-LPS (65,66). Colocalization of type IX secreted proteins and A-LPS is consistent with the finding that T9SS proteins use A-LPS as an anchor for attachment to the outer membrane (67)(68)(69). Interestingly, many bacteria have been shown to pack a preferential cargo of proteins into their OMVs (70)(71)(72)(73)(74)(75), suggesting that membrane remodeling occurs prior to, and may facilitate, vesiculation.…”

Section: Discussionsupporting

confidence: 62%

Identification of PGN_1123 as the Gene Encoding Lipid A Deacylase, an Enzyme Required for Toll-Like Receptor 4 Evasion, in Porphyromonas gingivalis

et al. 2019

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Removal of one acyl chain from bacterial lipid A by deacylase activity is a mechanism used by many pathogenic bacteria to evade the host's Toll-like receptor 4 (TLR4)-mediated innate immune response. In Porphyromonas gingivalis, a periodontal pathogen, lipid A deacylase activity converts a majority of the initially synthesized penta-acylated lipid A, a TLR4 agonist, to tetra-acylated structures, which effectively evade TLR4 sensing by being either inert or antagonistic at TLR4. In this paper, we report successful identification of the gene that encodes the P. gingivalis lipid A deacylase enzyme. This gene, PGN_1123 in P. gingivalis 33277, is highly conserved within P. gingivalis, and putative orthologs are phylogenetically restricted to the Bacteroidetes phylum. Lipid A of ΔPGN_1123 mutants is penta-acylated and devoid of tetra-acylated structures, and the mutant strain provokes a strong TLR4-mediated proinflammatory response, in contrast to the negligible response elicited by wild-type P. gingivalis. Heterologous expression of PGN_1123 in Bacteroides thetaiotaomicron promoted lipid A deacylation, confirming that PGN_1123 encodes the lipid A deacylase enzyme. IMPORTANCE Periodontitis, commonly referred to as gum disease, is a chronic inflammatory condition that affects a large proportion of the population. Porphyromonas gingivalis is a bacterium closely associated with periodontitis, although how and if it is a cause for the disease are not known. It has a formidable capacity to dampen the host's innate immune response, enabling its persistence in diseased sites and triggering microbial dysbiosis in animal models of infection. P. gingivalis is particularly adept at evading the host's TLR4-mediated innate immune response by modifying the structure of lipid A, the TLR4 ligand. In this paper, we report identification of the gene encoding lipid A deacylase, a key enzyme that modifies lipid A to TLR4-evasive structures.

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Section: Discussionsupporting

confidence: 62%

Identification of PGN_1123 as the Gene Encoding Lipid A Deacylase, an Enzyme Required for Toll-Like Receptor 4 Evasion, in Porphyromonas gingivalis

et al. 2019

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“…PPAD citrullinate host proteins 93 and is implicated in the autoimmune disease rheumatoid arthritis 94,95 . PPAD is produced in soluble and LPS-bound forms, but a single amino acid change (Gln 373 to Lys) in PPAD reduces the LPS-bound form of the protein 96,97 . Further, work is needed to clarify how PPAD and other P. gingivalis OMV proteins associate with LPS.…”

Section: Consequences Of Lps Modificationsmentioning

confidence: 99%

Pushing the envelope: LPS modifications and their consequences

2019

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The defining feature of the Gram-negative cell envelope is the presence of two cellular membranes with the specialized glycolipid lipopolysaccharide (LPS) exclusively found on the surface of the outer membrane. The surface layer of LPS contributes to the stringent permeability properties of the outer membrane which is particularly resistant to permeation of many toxic compounds, including antibiotics. As a common surface antigen, host immune cells recognize LPS and mount defenses to clear pathogenic organisms. To alter properties of the outer membrane or evade the host immune response, Gram-negative bacteria employ a wide variety of chemical modifications to alter LPS. Here we review key features and physiological consequences of LPS biogenesis and modifications.

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“…PPAD is detected in the outer membrane (OM) fractions of P. gingivalis and as a secreted enzyme, which is found in a soluble form and in association with outer membrane vesicles (OMVs) [120,151,152]. In most clinical isolates (termed type I isolates), extracellular PPAD is mainly found in secreted OMVs and to a minor extent in a soluble form.…”

Section: P Gingivalis In Ra Pathogenesismentioning

confidence: 99%

Rheumatoid Arthritis-Associated Mechanisms of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans

Gómez-Bañuelos

Mukherjee

Darrah

et al. 2019

JCM

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Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology characterized by immune-mediated damage of synovial joints and antibodies to citrullinated antigens. Periodontal disease, a bacterial-induced inflammatory disease of the periodontium, is commonly observed in RA and has implicated periodontal pathogens as potential triggers of the disease. In particular, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans have gained interest as microbial candidates involved in RA pathogenesis by inducing the production of citrullinated antigens. Here, we will discuss the clinical and mechanistic evidence surrounding the role of these periodontal bacteria in RA pathogenesis, which highlights a key area for the treatment and preventive interventions in RA.

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Dropping anchor: attachment of peptidylarginine deiminase via A-LPS to secreted outer membrane vesicles of Porphyromonas gingivalis

Cited by 26 publications

References 35 publications

Identification of PGN_1123 as the Gene Encoding Lipid A Deacylase, an Enzyme Required for Toll-Like Receptor 4 Evasion, in Porphyromonas gingivalis

Identification of PGN_1123 as the Gene Encoding Lipid A Deacylase, an Enzyme Required for Toll-Like Receptor 4 Evasion, in Porphyromonas gingivalis

Pushing the envelope: LPS modifications and their consequences

Rheumatoid Arthritis-Associated Mechanisms of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans

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