A Dock-and-Lock Mechanism Clusters ADAM10 at Cell-Cell Junctions to Promote α-Toxin Cytotoxicity

• Published in: Cell reports (Cambridge) Vol. 25; no. 8; pp. 2132 - 2147.e7
• Main Authors: Shah, Jimit, Rouaud, Florian, Guerrera, Diego, Vasileva, Ekaterina, Popov, Lauren M., Kelley, William L., Rubinstein, Eric, Carette, Jan E., Amieva, Manuel R., Citi, Sandra
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.11.2018; Elsevier
• Subjects: ADAM10; ADAM10 Protein - metabolism; Afadin; Bacterial Toxins - toxicity; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Cell Death - drug effects; cell junctions; Cell Line; cell-death; Cytoskeleton - drug effects; Cytoskeleton - metabolism; epithelium; Hemolysin Proteins - toxicity; Humans; Intercellular Junctions - drug effects; Intercellular Junctions - metabolism; Life Sciences; macropinocytosis; Microfilament Proteins - metabolism; PDZD11; Pinocytosis - drug effects; PLEKHA7; Protein Binding; Protein Domains; Protein Structure, Secondary; Staphylococcus auereus α-toxin; Tetraspanin; Tetraspanins - metabolism; cell junctions; macropinocytosis; PDZD11; Afadin; cell-death; ADAM10; epithelium; Staphylococcus auereus α-toxin; PLEKHA7; Tetraspanin; DAM10
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.10.088

We previously identified PLEKHA7 and other junctional proteins as host factors mediating death by S. aureus α-toxin, but the mechanism through which junctions promote toxicity was unclear. Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. ADAM10 is locked at junctions through binding of its cytoplasmic C terminus to afadin. Junctionally clustered ADAM10 supports the efficient formation of stable toxin pores. Instead, disruption of the PLEKHA7-PDZD11 complex inhibits ADAM10 and toxin junctional clustering. This promotes toxin pore removal from the cell surface through an actin- and macropinocytosis-dependent process, resulting in cell recovery from initial injury and survival. These results uncover a dock-and-lock molecular mechanism to target ADAM10 to junctions and provide a paradigm for how junctions regulate transmembrane receptors through their clustering. [Display omitted] •The α-toxin receptor ADAM10 is clustered at junctions by the PLEKHA7-PDZD11 complex•Tspan33 docks ADAM10 to junctions by binding to the WW domain of PLEKHA7•ADAM10 junctional clustering promotes the efficient formation of stable toxin pores•Loss of PLEKHA7-PDZD11 leads to toxin pore removal by endocytosis and cell survival Shah et al. clarify the mechanism through which adherens junctions render cells more susceptible to death by S. aureus α-toxin. PLEKHA7 and associated proteins create an Achilles heel by clustering the toxin receptor ADAM10 and toxin pores at junctions. Unclustered toxin pores are unstable and endocytosed, promoting cell survival.