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InlB, a surface protein of Listeria monocytogenes that behaves as an invasin and a growth factor

Unité des Interactions Bactéries-Cellules, Institut Pasteur, 28 Rue du Docteur Roux, 75724 Paris cedex 15, France

View larger version (15K): [in a new window]   Fig. 1. (A) Schematic domain organization of the mature InlB and HGF proteins. For InlB: Cp, cap region; LRR, leucine-rich repeats; IR, inter-repeat region; B, B-repeats; GW, GW-repeats. For HGF, N, N-terminal domain; K, kringles; SP, serine protease homology region. The mature heterodimer is formed by proteolytic digestion at an Arg-Val site and linkage of the resulting and ß chains by a disulfide bridge (S-S). (B) Crystal structure of the LRR domain of InlB [reproduced from (Marino et al., 1999)]. The domain consists of the N-terminal cap region (residues 36-76) and the LRR region (residues 77-242). and 310 helices are in cyan, ß strands are in red and loops are in green. Putative calcium ions bound to the cap region are shown as blue spheres.

View larger version (77K): [in a new window]   Fig. 2. InlB-induced actin-based processes. (A) InlB-mediated internalization by the `zipper-like' mechanism. On the left is a transmission electron microscopy section of an InlB-coated bead being internalized into an epithelial cell [reproduced from (Braun et al., 1998)]. The particle is engulfed within tightly adherent membranous structures before lying in a phagocytic vacuole. Note the presence of small membrane projections at the entry site of the particle. On the right, the F-actin phagocytic cup is stained with FITC-phalloidin (in green) at the entry site of two InlB-coated beads (in blue). (B) InlB-induced membrane ruffling in Vero cells. A cell untreated (left) or incubated with 4.5 nM purified InlB for 5 minutes (right) and stained with FITC-phalloidin to detect F-actin.

View larger version (32K): [in a new window]   Fig. 3. Role of cofilin during InlB-induced phagocytosis. Adapted from (Bierne et al., 2001). (1) Interaction of InlB with its receptors induces recruitment of the Arp2/3 complex (not shown) and of cofilin (represented by grey circles), which stimulate actin polymerization (represented by lines). LIM-kinase and the phosphatase SSH could be recruited to the phagocytic cup to regulate cofilin's activity. In a first step, LIM-kinase prevents excessive depolymerization of actin filaments by partly inactivating cofilin. Then, SSH would reactivate cofilin, which finally accumulates on the filaments and favors the disruption of the actin network during the retraction of the phagocytic cup and around the newly formed phagosome. Cofilin would thus be involved in both assembly and disassembly of the InlB-induced phagocytic cup. (2) Increasing the pool of active cofilin by expressing the constitutively active S3A cofilin or by inhibiting endogenous LIM-kinase blocks phagocytic cup formation, presumably because of an excess of depolymerizing activity. (3) Partial inactivation of cofilin by overexpressing LIMK1 induces an intense and disorganized accumulation of actin filaments at the phagocytic cup, preventing the engulfment of the particle into the cell.

View larger version (27K): [in a new window]   Fig. 4. The InlB-mediated signaling pathways. In bacteria present in the environment, InlB is buried into the bacterial cell wall, somehow protected from proteolytic degradation and external aggressive agents. Upon infection, in proximity with the targeted host cell, it may dissociate from the bacterial surface, by interacting with GAGs and gC1q-R and become accessible to the Met receptor. (1) The surface-exposed protein will trigger entry of the bacteria. (2) A pool of the protein may be released in the medium and induce signals as a prelude to or independently from entry. InlB-Met interactions induce recruitment of adapters proteins, some of which become tyrosine-phosphorylated, and recruitment and activation of the p85-p110 PI 3-kinase. Some downstream events induce actin cytoskeleton rearrangements involving Rho GTPases and cytoskeletal regulatory proteins, and membrane reorganization, leading to bacteria uptake. Other downstream events, involving activation of other enzymes, such as PLC or Akt, might affect the bacterial fate into the cell and/or the host cell behavior. Hashed arrows indicate hypothetical steps.