title: Group A streptococcal surface GAPDH, SDH, recognizes uPAR/CD87 as its receptor on the human pharyngeal cell and mediates bacterial adherence to host cells.
abstract: Streptococcal surface dehydrogenase (SDH) is a multifunctional, anchorless protein present on the surface of group A Streptococcus (GAS). It plays a regulatory role in GAS-mediated intracellular signaling events in human pharyngeal cells. Using ligand-binding assays, we have identified an approximately 55 kDa protein as an SDH-specific receptor protein on the surface of Detroit human pharyngeal cells. LC-MS/MS analyses identified this SDH-binding pharyngeal cell-surface-exposed membrane-bound protein as uPAR (urokinase plasminogen activator receptor)/CD87. Ligand-binding assays also revealed that only the N-terminal domain (D1) of uPAR bound to SDH. uPAR-D1 more specifically bound to the C-terminal alpha-helix and two immediate flanking regions of the S-loop of the SDH molecule. Site-directed mutagenesis in GAS resulting in SDH with altered C-terminal ends, and the removal of uPAR from pharyngeal cells by phosphatidylinositol-phopsholipase C treatment decreased GAS ability to adhere to pharyngeal cells. When compared to uninfected Detroit pharyngeal cells, GAS-infected pharyngeal cells showed a transient but a significant increase in the expression of uPAR-specific mRNA, and a prolonged recycling process of uPAR on the cell surface. Together, these results indicate that the specific streptococcal surface protein-pharyngeal cell receptor interaction mediated by SDH and uPAR is modulated during GAS infection of human pharyngeal cells. This interaction significantly contributes to bacterial adherence and thus may play a significant role in GAS pathogenesis by regulating intracellular signaling events in pharyngeal cells.
authors.affiliation: Laboratory of Bacterial Pathogenesis, Public Health Research Institute, At The International Center for Public Health, 225 Warren Street, Newark, NJ 07103-3535, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Jin
authors.forename: Youngmia P
authors.initials: YP
authors.lastname: Song
authors.forename: Gregory
authors.initials: G
authors.lastname: Boel
authors.forename: Jaspreet
authors.initials: J
authors.lastname: Kochar
authors.forename: Vijay
authors.initials: V
authors.lastname: Pancholi
mesh_terms: D000595:Amino Acid Sequence; D001422:Bacterial Adhesion; D002460:Cell Line; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010088:Oxidoreductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010614:Pharynx / Q000166:cytology* / Q000378:metabolism / Q000382:microbiology*; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D013297:Streptococcus pyogenes / Q000201:enzymology* / Q000378:metabolism
chemical_list: C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D010088:Oxidoreductases; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)