InlA-invasion Pathway





[Pizarro-Cerda et al., Cold Spring Harbor Perspectives in Medecine 2012]

Signaling cascades activated via the InlA-invasion pathways. Interaction of InlA and/or InlB with their respective host-cell surface receptors E-cadherin and Met induces ubiquitination of the receptors by the ubiquitin ligases Hakai in the case of E-cadherin or Cbl in the case of Met and subsequent recruitment of the clathrin endocytosis machinery (Dab2, clathrin, dynamin, Hip1R, MyoVI), which provides an initial platform for actin cytoskeleton polymerization. Downstream from E-cadherin, this first actin polymerization wave is activated by Src and cortactin, which promote recruitment of the Arp2/3 complex; association of β/α-catenins to the bacterial entry sites favors dynamic interactions between the E-cadherin cytoplasmic tail and the actin cytoskeleton. In the case of Met, actin polymerization can be first coordinated by dynamin and cortactin upstream of the Arp2/3 complex, and subsequently by a signaling cascade downstream from the type IA PI 3-kinase, which involves the small GTPases Rac1 and Cdc42, abi1, WAVE, and N-WASP (depending on the cell type); LIM-K and cofilin play a critical role in the depolymerization of actin to allow completion of the bacterial internalization process.





[Pizarro-Cerda et al., Journal of Pathology 2006]

The InlA-invasion pathway. (A) Schematic model of the main molecules required for the internalization of

L. monocytogenes via the InlA-invasion pathway: InlA interacts with its receptor E-cadherin, which recruits β- and α-catenin molecules to its cytoskeletal tail. This latter catenin interacts with actin, but also recruits the Rho GAP protein ARHGAP10, which is involved in the recruitment of vezatin and the unconventionalmyosin VIIA to the bacterial entry site, providing the motor force to internalize the bacteria by phagocytosis.

(B) Immunofluorescence showing the recruitment of the β- (green) and α- (red) catenins (overlay: yellow) to the entry site of L. monocytogenes (rod shape) in the human polarized intestinal cell line Caco-2. Co-localization of these molecules in the cellular adherens junctions is also observed. Reprinted from Cossart P et al: Invasion of mammalian cells by Listeria monocytogenes: functional mimicry to subvert cellular functions.

Trends in Cell Biology, Vol 13, No 1, 2003, pp 23–31, with permission from Elsevier.




[Hamon et al., Nature Reviews Microbiology 2006]

Adherens junction and internalin A (InlA)-induced bacterial entry. a) Adherens junctions hold adjacent cells together through the transmembrane protein epithelial cadherin (E-cadherin). The intracellular domain of E-cadherin recruits α-catenin and β-catenin, and α-catenin bridges the actin cytoskeleton and E-cadherin. Formins, which interact directly with α-catenin, are also essential for forming actin cables at cell–cell junctions, although the mechanism by which they achieve this is not understood. b) The receptor for the Listeria monocytogenes protein InlA is E-cadherin. Many components that are important for adherens junctions are recruited to the site of bacterial entry, where the cytoskeletal rearrangements that are required for invasion occur. ARF6, ADP-ribosylation factor 6; ARHGAP10, Rho GTPase-activating protein 10; Arp, actin-related protein; F-actin, filamentous actin; G-actin, globular actin.






[Cossart et al., Trends in Cell Biology 2003]

The bacterial entry process. (a,b) Entry of L. monocytogenes in a culture of human Caco-2 enterocytic cells. (a) Scanning electron microscopy. (b) Thin section. (c) Entry of Internalin-coated beads into L2071 transfected fibroblasts expressing human E-cadherin.






[Schubert et al., Cell 2002]

Structure of the functional domain of InlA (InlA’). a) Uncomplexed InlA′: cap domain-pink, LRR-domain-violet, Ig-like interrepeat domain-blue. β strands of the LRR are numbered; those of the Ig-like domain are indicated by letters. b) The complex InlA′/hEC1 viewed as in (A) and (C) rotated by 90°: hEC1 is rendered in green, strands indicated by letters.



[Lecuit et al., PNAS 2000]

E-cadherin, which is a calcium-dependent transmembrane protein, is involved in cell-cell adhesion. Its extracellular domain mediates homophilic interaction with E-cadherin expressed by adjacent cells. The association of E-cadherin cytoplasmic domain to cytoplasmic proteins called catenins is necessary for strong cell adhesion. E-cadherin C-terminus interacts directly with b-catenin, which in turn binds a-catenin, an actin-binding protein, thud providing a link between E-cadherin and the actin cytoskeleton. This interaction is critical for the establishment of adherens junctions and also for internalin mediated entry.


Updated on 13/05/2014



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