4 years ago

Stenotrophomonas maltophilia Serine Protease StmPr1 Induces Matrilysis, Anoikis, and Protease-Activated Receptor-2 Activation in Human Lung Epithelial Cells.

DuMont AL, Cianciotto NP
Stenotrophomonas maltophilia is an emerging, opportunistic nosocomial pathogen that can cause severe disease in immunocompromised individuals. We recently identified the StmPr1 and StmPr2 serine proteases as substrates of the Xps type II secretion system in S. maltophilia strain K279a. Here, we report that a third serine protease, StmPr3, is also secreted in an Xps-dependent manner. By constructing a panel of protease mutants in strain K279s, we were able to determine that StmPr3 contributes to the previously described Xps-mediated rounding and detachment of the A549 human lung epithelial cell line as well as Xps-mediated degradation of fibronectin, fibrinogen, and the cytokine interleukin-8. We also determined that StmPr1, StmPr2, and StmPr3 account for all Xps-mediated effects towards A549 cells, and that StmPr1 contributes the most to Xps-mediated activities. Thus, we purified StmPr1 from S. maltophilia strain K279a supernatant and evaluated the protease's activity towards A549 cells. Our analyses revealed that compared to subtilisin and trypsin, purified StmPr1 behaves more similarly to subtilisin. We also determined that purified StmPr1 likely induces cell rounding and detachment of A549 cells by targeting cell integrin-ECM connections (matrilysis) as well as adherence and tight junction proteins for degradation. In this study, we also identified anoikis as the mechanism by which StmPr1 induces death of A549 cells, and found that StmPr1 induces A549 IL-8 secretion via activation of protease-activated receptor-2. Altogether, these results suggest that the degradative and cytotoxic activities exhibited by StmPr1 may contribute to S. maltophilia pathogenesis in the lung by inducing tissue damage and inflammation.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28893914

DOI: PubMed:28893914

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