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Proteolytic Degradation of Fas Ligand by Yersinia pestis
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Proteolytic Degradation of Fas Ligand by Yersinia pestis
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Proteolytic Degradation of Fas Ligand by Yersinia pestis
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Dissertation
Proteolytic Degradation of Fas Ligand by Yersinia pestis
2013
Overview
Yersinia pestis, the causative agent of the disease plague, produces the plasminogen activator Pla, a surface-exposed protease that is critical for the progression of the pneumonic form of the disease. Pla is required for bacterial outgrowth in the lungs and to elicit the massive host inflammatory response observed during the later stages of infection. However, the specific host substrates cleaved by Pla to modulate these innate immune responses have not yet been reported. As a means of substrate discovery, a proteomic-scale approach utilizing a peptide microarray was used to identify additional host factors targeted by this protease. By this method, we discovered that Pla directly inactivates the host apoptotic signaling molecule Fas ligand (FasL). Pla is sufficient for FasL cleavage as demonstrated utilizing E. coli inducibly expressing pla, while the catalytic activity of Pla was confirmed as necessary using active site point mutants. FasL glycosylation is required for recognition by Pla, which likely cleaves FasL at multiple sites for its complete inactivation. Functionally, degradation of FasL by Pla prevents the induction of Fas-dependent caspase-3/7 activation and apoptotic signaling cascades, which have been implicated as otherwise protective to the host during bacterial pneumonias. In a murine model of pneumonic plague, the loss of active FasL leads to enhanced outgrowth of Y. pestis in the lungs, reduced cytokine secretion, and elimination of caspase-3/7 activation. In the absence of Pla, increased caspase-3/7 activation is observed in neutrophils recruited to inflammatory lesions within the lungs. Specific inhibition of caspase-3/7 with the peptide inhibitor DEVD recapitulates the loss of FasL by enhancing bacterial outgrowth and reducing cytokine secretion, indicating that the cleavage of FasL by Pla overcomes these caspase-3/7-dependent host defenses. This study provides the first example of a bacterium targeting the Fas-FasL signaling pathway through the specific degradation of FasL, and presents a previously unidentified pathogenic mechanism by which Y. pestis controls host cell death and inflammation during pneumonia.
