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

PLoS Pathogens

Sabine Patot¹  Ina Attrée²  Philippe Huber²  Emeline Reboud²  Benoît Béganton²  Stéphanie Bouillot² 

[1]CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France

[2]Université Grenoble Alpes, CNRS ERL5261, CEA BIG-BCI, INSERM UMR1036, Grenoble, France

关键词: Cadherins;    Toxins;    Cell membranes;    Pseudomonas aeruginosa;    Serratia marcescens;    Endothelial cells;    Host cells;    Intracellular membranes;   

DOI  :  10.1371/journal.ppat.1006579

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY