5 years ago

<i>Pseudomonas aeruginosa</i> ExlA and <i>Serratia marcescens</i> ShlA trigger cadherin cleavage by promoting calcium influx and ADAM10 activation

Benoît Béganton, Sabine Patot, Emeline Reboud, Philippe Huber, Ina Attrée, Stéphanie Bouillot

by Emeline Reboud, Stéphanie Bouillot, Sabine Patot, Benoît Béganton, Ina Attrée, Philippe Huber

Pore-forming toxins are potent virulence factors secreted by a large array of bacteria. Here, we deciphered the action of ExlA from Pseudomonas aeruginosa and ShlA from Serratia marcescens on host cell-cell junctions. ExlA and ShlA are two members of a unique family of pore-forming toxins secreted by a two-component secretion system. Bacteria secreting either toxin induced an ExlA- or ShlA-dependent rapid cleavage of E-cadherin and VE-cadherin in epithelial and endothelial cells, respectively. Cadherin proteolysis was executed by ADAM10, a host cell transmembrane metalloprotease. ADAM10 activation is controlled in the host cell by cytosolic Ca2+ concentration. We show that Ca2+ influx, induced by ExlA or ShlA pore formation in the plasma membrane, triggered ADAM10 activation, thereby leading to cadherin cleavage. Our data suggest that ADAM10 is not a cellular receptor for ExlA and ShlA, further confirming that ADAM10 activation occurred via Ca2+ signalling. In conclusion, ExlA- and ShlA-secreting bacteria subvert a regulation mechanism of ADAM10 to activate cadherin shedding, inducing intercellular junction rupture, cell rounding and loss of tissue barrier integrity.

Publisher URL: http://journals.plos.org/plosone/article

DOI: 10.1371/journal.ppat.1006579

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