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J. Biol. Chem., Vol. 281, Issue 32, 22453-22463, August 11, 2006

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Candida albicans Cell Wall Ssa Proteins Bind and Facilitate Import of Salivary Histatin 5 Required for Toxicity^*

Xuewei S. Li, Jianing N. Sun, Kazuko Okamoto-Shibayama, and Mira Edgerton¹

From the Departments of Oral Biology and Restorative Dentistry, School of Dental Medicine, State University of New York, Buffalo, New York 14214

Fungicidal activity of Hst 5 is initiated by binding to cell surface proteins on Candida albicans, followed by intracellular transport to cytoplasmic effectors leading to cell death. As we identified heat shock 70 proteins (Ssa1p and/or Ssa2p) from C. albicans lysates that bind Hst 5, direct interactions between purified recombinant Ssa proteins and Hst 5 were tested by pull-down and yeast two-hybrid assays. Pulldown of both native complexes and those stabilized by cross-linking demonstrated higher affinity of Hst 5 for Ssa2p than for Ssa1p, in agreement with higher levels of interactions between Ssa2p and Hst 5 measured by yeast two-hybrid analyses. C. albicans ssa1 and ssa2 mutants were constructed to examine Hst 5 binding, translocation, and candidacidal activities. Both ssa1 and ssa2 mutants were indistinguishable from wild-type cells in growth and hyphal formation. However, C. albicans ssa2 mutants were highly resistant to the candidacidal activity of Hst 5, although the ssa1 mutant did not have any significant reduction in killing by Hst 5. Total cellular binding of ¹²⁵I-Hst 5 in the ssa2 mutant was reduced to one-third that of wild-type cells, in contrast to the ssa1 mutant whose total cellular binding of Hst 5 was similar to the wild-type strain. Intracellular transport of Hst 5 was significantly impaired in the ssa2 mutant strain, but only mildly so in the ssa1 mutant. Thus, C. albicans Ssa2p facilitates fungicidal activity of Hst 5 in binding and intracellular translocation, whereas Ssa1p appears to have a lesser functional role in Hst 5 toxicity.

Received for publication, April 27, 2006 , and in revised form, May 18, 2006.

^* This work was supported by United States Public Health Service Grant NIDCR DE10641 from the National Institutes of Health (to M. E.). 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.

¹ To whom correspondence should be addressed: Dept. of Oral Biology, 310 Foster Hall, State University of New York, Main St. Campus, 3435 Main St., Buffalo, NY 14214. Tel.: 716-829-3067; Fax: 716-829-3942; E-mail: edgerto{at}buffalo.edu.

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