PI(4,5)P₂-associated intoxication model: intracellularly-induced systemic death.

<p><b>A</b>) After translocation into the host cytoplasm by T3SS, ExoU (U) is postulated to bind to PI(4,5)P₂ residing on the inner leaflet of the plasma membrane. The PLA₂ activity of ExoU is activated by a cofactor (Co), ubiquitin or ubiquitinated proteins. <b>B</b>) ExoU hydrolyzes PI(4,5)P₂ and/or other phospholipid species (shown as Xs), leaving lyso-phospholipids, destabilizing the membrane. Reduction of PI(4,5)P₂ disrupts the anchoring and interaction between the focal adhesion, cytoskeletal structure, and plasma membrane, possibly through a cell signaling pathway. Cells round due to the weakened adhesion capability and actin filament depolymerization, leading to cytoskeletal collapse. The outer leaflet of the plasma membrane is intact at this stage. <b>C</b>) At a middle stage of infection, the plasma membrane starts to bleb, facilitating further membrane damage. <b>D</b>) During a late stage of infection, the outer leaflet of the plasma membrane is compromised, allowing the influx of an impermeable nucleic acid dye and staining of the nucleus (green), consequently large molecules (e.g. LDH) are released from lysed cells.