Candida albicans aspartic proteinase cleaves and inactivates human epidermal cysteine proteinase inhibitor, cystatin A

Abstract

It is known that the cysteine proteinase inhibitor, cystatin, has a defence function against exogenous pathogens. Human epidermal cysteine proteinase inhibitor, cystatin A, which is a member of the cystatin family, is localized in the upper epidermal layer. In this study, the relationship between cystatin A and Candida aspartic proteinase (CAP), a putative Candida virulence factor, was studied. CAP activity was not affected by human epidermal cystatin A, while 90% of cystatin A activity was lost after incubation with CAP for 12 h at 37 "C. Human epidermal cystatin A was cleaved into small peptides by CAP, and the released peptides had no cystatin activity. These results suggest that CAP may induce an imbalance between cysteine proteinase and its inhibitor in cutaneous Candida infectious lesions through the degradation and inactivation of epidermal cystatin A.

Evidence that Members of the Secretory Aspartyl Proteinase Gene Family, in ParticularSAP2,Are Virulence Factors forCandidaVaginitis

“…Because one major mechanism whereby Sap could express the virulence potential of C. albicans is the degradation of defensive host components [20][21][22][23][24], it was of obvious importance to examine active Sap production during the vaginal infection. To this aim, Sap enzyme activity was assessed by the capacity of the vaginal fluid to degrade a model substrate, such as BSA, in a pepstatin-sensitive manner [7,29].…”

“…Sap constitute a family of isoenzymes encoded by at least nine genes (SAP) that are differentially expressed in vitro and in vivo [14][15][16][17][18][19]. These enzymes are able to degrade several host defensive factors [20][21][22][23][24], and there is some initial evidence that drug-or antibody-mediated inhibition of this enzymatic activity may have a curative effect on experimental candidiasis [25,26].…”

Candida albicans proteinases: resolving the mystery of a gene family

“…albicans Saps may also act on host proteolytic cascades with numerous effects, which have no obvious advantage for the fungus. For example, Sap2 can activate host protein precursors of the blood clotting cascade (Kaminishi et al, 1994), inactivate the epidermal cysteine proteinase inhibitor cystatin A (Tsushima et al, 1994), and cleave human endothelin-1 precursor (a vasoconstrictive peptide) to alter vascular homeostasis (Tsushima & Mine, 1995). Such activities may be responsible for the enhanced overall circulating proteolytic activity observed in traumatized mice challenged with C. albicans (Neely et al, 1994).…”

Candida albicansSecreted Aspartyl Proteinases in Virulence and Pathogenesis

“…albicans proteinases may also evade host defenses by directly degrading molecules such as salivary lactoferrin, lactoperoxidase, cathepsin D (an intracellular lysosomal enzyme of leukocytes), and complement (72,94,106). In addition, Sap2 can degrade ␣ 2 -macroglobulin, a natural proteinase inhibitor in human plasma (187), and cystatin A, a cysteine proteinase inhibitor found in human epidermal tissues and fluids (238). Furthermore, the proinflammatory cytokine interleukin-1␤ can be activated from its precursor by Sap2, suggesting a role for proteinases in the activation and maintenance of the inflammatory response at epithelial surfaces in vivo (8).…”