{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T23:40:45Z","timestamp":1783381245445,"version":"3.54.6"},"reference-count":43,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2013,2,19]],"date-time":"2013-02-19T00:00:00Z","timestamp":1361232000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2013,6]]},"abstract":"<jats:p>\n                    Systemic infection by the pathogenic yeast\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    produces high mortality in immune\u2010compromised 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\u20136 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\u2010containing peptides or by substituting RGD motifs of these Saps. The internalization of Saps 4\u20136 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\n                    <jats:italic>via<\/jats:italic>\n                    caspase activation. Sap 2 and mutated Saps 4\u20136 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\u201015 cells. Mucosal lesions from this fundamental new mechanism may permit\n                    <jats:italic>C. albicans<\/jats:italic>\n                    to enter the body and may be used to attack cells in immune defense during systemic infections. RGD\u2010motif may also be incorporated in Sap inhibitors for Candidiasis drugs targeting to lysosomes.\u2014Wu, H., Downs, D., Ghosh, K., Ghosh, A. K., Staib, P., Monod, M., and Tang, J.\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    secreted aspartic proteases 4\u20136 induce apoptosis of epithelial cells by a novel Trojan horse mechanism.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    27, 2132\u20132144 (2013).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.12-214353","type":"journal-article","created":{"date-parts":[[2013,2,20]],"date-time":"2013-02-20T01:55:12Z","timestamp":1361325312000},"page":"2132-2144","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["<i>Candida albicans<\/i>\n                    secreted aspartic proteases 4\u20136 induce apoptosis of epithelial cells by a novel Trojan horse 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