Synergy between the N- and C-terminal domains of InIB for efficient invasion of non-phagocytic cells by Listeria monocytogenes

InIB is a Listeria monocytogenes protein promoting entry in non-phagocytic cells, and has been shown recently to activate the hepatocyte growth factor receptor (HGFR or Met). The N-terminal domain of InIB (LRRs) binds and activates Met, whereas the C-terminal domain of InIB (GW modules) mediates loose attachment of InIB to the listerial surface. As HGF activation of Met is tightly controlled by glycosaminoglycans (GAGs), we tested if GAGs also modulate the Met-InIB interactions. We show that InIB-dependent invasion of non-phagocytic cells decreases up to 10 times in the absence of GAGs, and that soluble heparin releases InlB from the bacterial surface and promotes its clustering. Furthermore, we demonstrate that InlB binds cellular GAGs by its GW modules, and that this interaction is required for efficient InIB-mediated invasion. Therefore, GW modules have an unsuspected dual function: they attach InIB to the bacterial surface and enhance entry triggered by the LRRs domain. Our results thus provide the first evidence for a synergy between two host factor-binding domains of a bacterial invasion protein, and reinforce similarities between InlB and mammalian growth factors.