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Upon activation, vinculin reinforces cytoskeletal anchorage during cell adhesion. Activating ligands classically disrupt intramolecular interactions between the vinculin head and tail domains that bind to actin filaments. Here, we show that Shigella IpaA triggers major allosteric changes in the head domain, leading to vinculin homo-oligomerization. Through the cooperative binding of its three vinculin-binding sites (VBSs), IpaA induces a striking reorientation of the D1 and D2 head subdomains associated with vinculin oligomerization. IpaA thus acts as a catalyst producing vinculin clusters that bundle actin at a distance from the activation site and trigger the formation of highly stable adhesions resisting the action of actin relaxing drugs. Unlike canonical activation, vinculin homo-oligomers induced by IpaA appear to keep a persistent imprint of the activated state in addition to their bundling activity, accounting for stable cell adhesion independent of force transduction and relevant to bacterial invasion. [Display omitted] • Shigella IpaA induces vinculin oligomerization via the D1D2 head subdomains • IpaA-induced vinculin oligomers promote actin bundling • IpaA stimulates the formation of highly stable focal adhesions • Focal adhesions triggered by IpaA form independent of acto-myosin contraction Valencia-Gallardo et al. show that the Shigella invasion effector IpaA induces major conformational changes in the vinculin head domain leading to vinculin oligomerization and actin filament bundling. This non-canonical mode of vinculin activation is required for bacterial invasion and may also be pertinent for the formation of cell adhesion structures. [ABSTRACT FROM AUTHOR]

The actin cytoskeleton is key to the barrier function of epithelial cells, by permitting the establishment and maintenance of cell-cell junctions and cell adhesion to the basal matrix. Actin exists under monomeric and polymerized filamentous form and its polymerization following activation of nucleation promoting factors generates pushing forces, required to propel intracellular microorganisms in the host cell cytosol or for the formation of cell extensions that engulf bacteria. Actin filaments can associate with adhesion receptors at the plasma membrane via cytoskeletal linkers. Membrane anchored to actin filaments are then subjected to the retrograde flow that may pull membrane-bound bacteria inside the cell. To induce its internalization by normally non-phagocytic cells, bacteria need to establish adhesive contacts and trick the cell into apply pulling forces, and/or to generate protrusive forces that deform the membrane surrounding its contact site. In this review, we will focus on recent findings on actin cytoskeleton reorganization within epithelial cells during invasion and cell-to-cell spreading by the enteroinvasive pathogen S higella, the causative agent of bacillary dysentery. [ABSTRACT FROM AUTHOR]