The secreted C. albicans protein Pra1 disrupts complement by targeting C3 in multiple manners.Graphical abstract
1) Secreted Pra1 directly cleaves C3 and generates C3aL and C3bL fragments.Graphical abstract
2) Pra1 further degrades the C3aL activation fragment.Graphical abstract
3) C3bL is degraded by human protease Factor I assisted by the cofactor Factor H. In addition, Pra1 binds to the activation fragments C3a and C3b which are generated by the human convertase and blocks their effector functions.Graphical abstract
4) Pra1 blocks antifungal activity of C3a and 5) inhibits C3b opsonization.
Candida albicans the most frequently isolated clinical fungal pathogen can cause local as well as systemic and life-threatening infections particularly in immune-compromised individuals. A better and more detailed understanding how C. albicans evades human immune attack is therefore needed for identifying fungal immune-evasive proteins and develop new therapies. Here, we identified Pra1, the pH-regulated C. albicans antigen as a hierarchical complement inhibitor that targets C3, the central human complement component. Pra1 cleaved C3 at a unique site and further inhibited effector function of the activation fragments. The newly formed C3a-like peptide lacked the C-terminal arginine residue needed for C3a-receptor binding and activation. Moreover, Pra1 also blocked C3a-like antifungal activity as shown in survival assays, and the C3b-like molecule formed by Pra1 was degraded by the host protease Factor I. Pra1 also bound to C3a and C3b generated by human convertases and blocked their effector functions, like C3a antifungal activity shown by fungal survival, blocked C3a binding to human C3a receptor-expressing HEK cells, activation of Fura2-AM loaded cells, intracellular Ca2+ signaling, IL-8 release, C3b deposition, as well as opsonophagocytosis and killing by human neutrophils. Thus, upon infection C. albicans uses Pra1 to destroy C3 and to disrupt host complement attack. In conclusion, candida Pra1 represents the first fungal C3-cleaving protease identified and functions as a fungal master regulator of innate immunity and as a central fungal immune-escape protein.