title: Candida albicans secreted aspartic proteases 4-6 induce apoptosis of epithelial cells by a novel Trojan horse mechanism.
abstract: Systemic infection by the pathogenic yeast Candida albicans produces high mortality in immune-compromised people. Such infection starts with the penetration of the organism at the mucosal surfaces, facilitated by the secreted aspartic proteases (Saps) 4, 5, and 6. The functional mechanism of these virulence factors is unclear. We discovered that Saps 4-6 each contains amino acid motifs RGD/KGD to bind integrins on epithelial cell A549 and are internalized to endosomes and lysosomes. These processes are inhibited by RGD-containing peptides or by substituting RGD motifs of these Saps. The internalization of Saps 4-6 results in partial permeabilization of lysosomal membranes, measured by the redistribution of the lysosomal tropic dye acridine orange to the cytosol, and the triggering of apoptosis via caspase activation. Sap 2 and mutated Saps 4-6 contain no RGD motif, are ineffective in these processes, and a proteolytic inhibitor abolished Sap 4 activity in lysosome permeabilization. Same results were also seen for human tongue keratinocyte SCC-15 cells. Mucosal lesions from this fundamental new mechanism may permit C. albicans to enter the body and may be used to attack cells in immune defense during systemic infections. RGD-motif may also be incorporated in Sap inhibitors for Candidiasis drugs targeting to lysosomes.
authors: Protein Studies Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors: Hao
authors: H
authors: Wu
authors: Deborah
authors: D
authors: Downs
authors: Koena
authors: K
authors: Ghosh
authors: Arun K
authors: AK
authors: Ghosh
authors: Peter
authors: P
authors: Staib
authors: Michel
authors: M
authors: Monod
authors: Jordan
authors: J
authors: Tang
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002176:Candida albicans / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity*; D002177:Candidiasis / Q000201:enzymology / Q000209:etiology; D002460:Cell Line; D004847:Epithelial Cells / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000235:genetics; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D014774:Virulence
chemical_list: D005656:Fungal Proteins; D016023:Integrins; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D016282:Aspartic Acid Endopeptidases; C086392:SAP4 protein, Candida albicans; C090755:SAP5 protein, Candida albicans; C582621:SAP6 protein, Candida albicans
keywords: infectious diseases; integrins; lysosome membrane; virulence factors