Working model explaining TJ disruption by the EhCPADH112 complex.

<p><b>A)</b> TJs are formed at the border between the apical and the basolateral sides of neighbouring cells. Among their integral components are occludin and claudin-1 that interact with the actin cytoskeleton via members of the ZO family of proteins. <b>B)</b> Trophozoites reach the intercellular region of epithelial cells exposing the EhCPADH112 complex (red rectangles and green cylinders) at their plasma membrane or secreting it into the media. Alternatively, the EhCPADH112 complex could undergo conformational changes resulting in the separation of EhCP112 (green cylinders) from EhADH112 (red rectangles). Next, EhCPADH112, EhCP112 and EhADH112 bind to occludin and claudin-1 causing disassembly of epithelial cell-cell interactions and a drop in TER. Once inside epithelial cells, <i>Entamoeba</i> proteases such as EhCP112 can degrade intracellular TJ proteins such as ZO-1 and ZO-2. As a consequence of TJ disruption, other parasite proteins may enter through the paracellular pathway to trigger epithelial damage.