IQGAP 1 mediates the disruption of adherens junctions to promote E scherichia coli K 1 invasion of brain endothelial cells

Summary The transcellular entry of E scherichia coli K 1 through human brain microvascular endothelial cells ( HBMEC ) is responsible for tight junction disruption, leading to brain oedema in neonatal meningitis. Previous studies demonstrated that outer membrane protein A ( OmpA ) of E . coli K 1 interacts with its receptor, E cgp96, to induce PKC ‐α phosphorylation, adherens junction ( AJ ) disassembly (by dislodging β‐catenin from VE ‐cadherin), and remodelling of actin in HBMEC . We report here that IQGAP 1 mediates β‐catenin dissociation from AJ s to promote actin polymerization required for E . coli K 1 invasion of HBMEC . Overexpression of C ‐terminal truncated IQGAP 1 ( IQ Δ C ) that cannot bind β‐catenin prevents both AJ disruption and E . coli K 1 entry. Of note, phospho‐ PKC ‐α interacts with the C ‐terminal portion of E cgp96 as well as with VE ‐cadherin after IQGAP 1‐mediated AJ disassembly. HBMEC overexpressing either C ‐terminal truncated E cgp96 ( E cgp96Δ200) or IQ Δ C upon infection with E . coli showed no interaction ofphospho‐ PKC ‐α with E cgp96. These data indicate that the binding of OmpA to E cgp96 induces PKC ‐α phosphorylation and association of phospho‐ PKC ‐α with E cgp96, and then signals IQGAP 1 to detach β‐catenin from AJ s. Subsequently, IQGAP 1/β‐catenin bound actin translocates to the site of E . coli K 1 attachment to promote invasion.