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

> **NIH NIH R21** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2022 · $199,375

## Abstract

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.

## Key facts

- **NIH application ID:** 10428637
- **Project number:** 5R21DE030245-02
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Mira Edgerton
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $199,375
- **Award type:** 5
- **Project period:** 2021-07-01 → 2025-12-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428637

## Citation

> US National Institutes of Health, RePORTER application 10428637, Candida albicans secreted protease Sap6 engages epithelial protease-activated receptors PAR2 and NLRP3 (5R21DE030245-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10428637. Licensed CC0.

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