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J. Biol. Chem., Vol. 280, Issue 11, 10455-10461, March 18, 2005

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N-cadherin Mediates Endocytosis of Candida albicans by Endothelial Cells^*

Quynh T. Phan, Rutillio A. Fratti, Nemani V. Prasadarao¶, John E. Edwards, Jr.||**, and Scott G. Filler, Supported by the Burroughs Wellcome Fund New Investigator Award in Molecular Pathogenic Mycology||

From the St. John's Cardiovascular Research Center, Division of Infectious Diseases, Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, ^¶Division of Infectious Diseases, Children's Hospital and the Keck School of Medicine, University of Southern California, Los Angeles, California 90027, and ^||David Geffen School of Medicine at UCLA, Los Angeles, California 90024

Candida albicans is the most common cause of fungal bloodstream infections. To invade the deep tissues, blood-borne organisms must cross the endothelial cell lining of the vasculature. We have found previously that C. albicans hyphae, but not blastospores, invade endothelial cells in vitro by inducing their own endocytosis. Therefore, we set out to identify the endothelial cell receptor that mediates the endocytosis of C. albicans. We determined that endocytosis of C. albicans was not mediated by bridging molecules in the serum and that it was partially dependent on the presence of extracellular calcium. Using an affinity purification procedure, we discovered that endothelial cell N-cadherin bound to C. albicans hyphae but not blastospores. N-cadherin also co-localized with C. albicans hyphae that were being endocytosed by endothelial cells. Chinese hamster ovary (CHO) cells expressing human N-cadherin endocytosed significantly more C. albicans hyphae than did CHO cells expressing either human VE-cadherin or no human cadherins. The expression of N-cadherin by the CHO cells resulted in enhanced endocytosis of hyphae, but not blastospores, indicating the selectivity of the N-cadherin-mediated endocytosis. Down-regulation of endothelial cell N-cadherin expression with small interfering RNA significantly inhibited the endocytosis of C. albicans hyphae. Therefore, a novel function of N-cadherin is that it serves as an endothelial cell receptor, which mediates the endocytosis of C. albicans.

Received for publication, November 8, 2004

^* This work was supported by Public Health Service Grants R01 AI054928, R01 AI19990, and MO1 RR00425 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Biochemistry, Dartmouth Medical School, 7200 Vail Bldg., Hanover, NH 03755.

^** Holds an unrestricted grant award in Infectious Diseases from Bristol Myers Squibb under the Freedom to Discover Program.

To whom correspondence should be addressed: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson St., Torrance, CA 90502. Tel.: 310-222-6426; Fax: 310-782-2016; E-mail: sfiller{at}ucla.edu.

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