Candida albicans secreted protease Sap6 engages epithelial protease-activated receptors PAR2 and NLRP3

白色念珠菌的致病性与其从酵母到酵母的形态转化有关

Candida albicans pathogenicity is associated with its morphological transformation from yeast to production of filamentous hyphae. Secretion of hyphal-specific proteins, particularly the aspartyl protease Sap6, is a key marker of its transition from commensalism to virulence. Sap6 contains both a proteinase domain and an RGDRGD integrin-binding motif adjacent to its catalytic domain. We found that rSap6 added to primary oral epithelial cells (OECs) elicited IL1β secretion typical of NLRP3 signaling but also produced IL-8. Sap6 added to OECs induced phosphorylation of p38 and IL-8 production through the protease- activated receptor (PAR2). PAR2 signaling was lost upon heat inactivation of Sap6, while NLRP signaling was reduced upon deletion of Sap6 RGD-binding sites, leading to our hypothesis that both Sap6 proteolytic and RGD-mediated mechanisms are involved in sensing levels of this fungal secreted protein by OECs. We will test this hypothesis by identifying the proteolytic mechanism for Sap6 activated PAR2 MAPKinase signaling in OECs in Aim1, and assessing the contribution of the Sap6 integrin-binding RGD motif in NLRP3 inflammasome activation and apoptosis in Aim 2. This work will establish PAR2 and integrin/NLRP3 as cell surface receptors for C. albicans Sap6 and define their role in modulating host inflammatory responses to fungal proteins in OECs. The long-range goal of this project will be to activate/deactivate PAR2 receptors or NLRP3 signaling as a means of modulating host inflammation as an avenue for treatment of candidiasis.