Скачать или смотреть Jimit Shah - Junctional clustering of ADAM10 by the PLEKHA7-PDZD11 complex...

Unctional clustering of ADAM10 by the PLEKHA7-PDZD11 complex through Tetraspanin33 promotes cell death by Staphylococcus aureus α-toxin

Although transmembrane proteins of cell-cell junctions can
function as receptors for viruses and bacterial toxins, the role of cytoplasmic junctional proteins in host-pathogen interactions is poorly understood. The cytoplasmic junctional protein PLEKHA7 was identified as a key host factor for cell death caused by Staphylococcus aureus α-toxin, through a screen in Hap1 cells. Here we clarify the mechanism through which PLEKHA7 promotes cell death. Using immunofluorescence analysis, we demonstrate that PLEKHA7 and its interacting partner PDZD11 cluster the alpha-toxin receptor ADAM10 and its partner Tspan33, localizing toxin pores at the zonula ahaerens of epithelial kidney cells and regions of cell contact of Hap1 cells. Toxin pores clustered at junctions are more stable, and cause cell death at low/intermediate toxin doses, suggesting that they have intrinsically enhanced cytotoxic activity. Proximity ligation and
co-immunoprecipitation assays show that PLEKHA7 associates with the ADAM10-Tspan33
complex in a PDZD11-dependent manner, and GST pulldowns show that PDZD11 promotes the interaction of N-terminal
fragments of PLEKHA7 with the C-terminal cytoplasmic domains
of Tspan33 and ADAM10. In summary, the PLEKHA7/PDZD11 complex controls the function of a pore-forming toxin by acting
as a scaffold that organizes the surface distribution of its receptor
complex. These results provide a novel molecular mechanism underlying host-pathogen interactions, and a new function for cytoplasmic components of adherens junctions
.