Inactivation of epidermal growth factor by Porphyromonas gingivalis as a potential mechanism for periodontal tissue damage

Infect Immun. 2013 Jan;81(1):55-64. doi: 10.1128/IAI.00830-12. Epub 2012 Oct 22.

Abstract

Porphyromonas gingivalis is a Gram-negative bacterium associated with the development of periodontitis. The evolutionary success of this pathogen results directly from the presence of numerous virulence factors, including peptidylarginine deiminase (PPAD), an enzyme that converts arginine to citrulline in proteins and peptides. Such posttranslational modification is thought to affect the function of many different signaling molecules. Taking into account the importance of tissue remodeling and repair mechanisms for periodontal homeostasis, which are orchestrated by ligands of the epidermal growth factor receptor (EGFR), we investigated the ability of PPAD to distort cross talk between the epithelium and the epidermal growth factor (EGF) signaling pathway. We found that EGF preincubation with purified recombinant PPAD, or a wild-type strain of P. gingivalis, but not with a PPAD-deficient isogenic mutant, efficiently hindered the ability of the growth factor to stimulate epidermal cell proliferation and migration. In addition, PPAD abrogated EGFR-EGF interaction-dependent stimulation of expression of suppressor of cytokine signaling 3 and interferon regulatory factor 1. Biochemical analysis clearly showed that the PPAD-exerted effects on EGF activities were solely due to deimination of the C-terminal arginine. Interestingly, citrullination of two internal Arg residues with human endogenous peptidylarginine deiminases did not alter EFG function, arguing that the C-terminal arginine is essential for EGF biological activity. Cumulatively, these data suggest that the PPAD-activity-abrogating EGF function in gingival pockets may at least partially contribute to tissue damage and delayed healing within P. gingivalis-infected periodontia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arginine / metabolism
  • Bacteroidaceae Infections / metabolism*
  • Bacteroidaceae Infections / microbiology
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Epidermal Growth Factor / metabolism*
  • Epithelium / metabolism
  • Epithelium / microbiology
  • ErbB Receptors / metabolism
  • Fibroblasts / metabolism
  • Fibroblasts / microbiology
  • Humans
  • Hydrolases / metabolism
  • Interferon Regulatory Factor-1 / metabolism
  • Periodontitis / metabolism
  • Periodontitis / microbiology
  • Periodontium / metabolism*
  • Periodontium / microbiology*
  • Porphyromonas gingivalis / metabolism*
  • Protein-Arginine Deiminases
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • Wound Healing

Substances

  • Interferon Regulatory Factor-1
  • SOCS3 protein, human
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Epidermal Growth Factor
  • Arginine
  • ErbB Receptors
  • Hydrolases
  • Protein-Arginine Deiminases