Syndecan-1 and syndecan-4 can mediate the invasion of OpaHSPG-expressing Neisseria gonorrhoeae into epithelial cells

Neisseria gonorrhoeae ( Ngo ) expressing the outer membrane protein Opa_HSPG can adhere to and invade epithelial cells via binding to heparan sulphate proteoglycan (HSPG) receptors. In this study, we have investigated the role of syndecan-1 and syndecan-4, two members of the HSPG family, in the uptake of Ngo by epithelial cells. When overexpressed in HeLa cells, both syndecans co-localize with adherent Ngo on the host cell surface. This overexpression of syndecan-1 and syndecan-4 leads to a three- and sevenfold increase in Ngo invasion respectively. In contrast, transfection with the syndecan-1 and syndecan-4 mutant constructs lacking the intracellular domain results in an abrogation of the invasion process, characteristic of a dominant-negative mode of action. A concomitant loss of the capacity to mediate Ngo uptake was also observed with syndecan-4 mutant constructs carrying lesions in the dimerization motif necessary for the binding of protein kinase C (PKC) and phosphatidylinositol 4,5-bisphosphate (PIP₂), and mutants that are deficient in a C-terminal EFYA amino acid motif responsible for binding to syntenin or CASK. We conclude that syndecan-1 and syndecan-4 can both mediate Ngo uptake into epithelial cells, and that their intracellular domains play a crucial role in this process, perhaps by mediating signal transduction or anchorage to the cytoskeleton.