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J. Biol. Chem., Vol. 281, Issue 52, 40399-40411, December 29, 2006

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The CRH Family Coding for Cell Wall Glycosylphosphatidylinositol Proteins with a Predicted Transglycosidase Domain Affects Cell Wall Organization and Virulence of Candida albicans^*

Giacomo Pardini¹, Piet W. J. De Groot, Alix T. Coste, Mahir Karababa, Frans M. Klis, Chris G. de Koster, and Dominique Sanglard²

From the Institute of Microbiology, University Hospital Lausanne, CH-1011 Lausanne, Switzerland and Swammerdam Institute for Life Sciences, University of Amsterdam, 1018 WV Amsterdam, Netherlands

In Candida albicans UTR2 (CSF4), CRH11, and CRH12 are members of a gene family (the CRH family) that encode glycosylphosphatidylinositol-dependent cell wall proteins with putative transglycosidase activity. Deletion of genes of this family resulted in additive sensitivity to compounds interfering with normal cell wall formation (Congo red, calcofluor white, SDS, and high Ca²⁺ concentrations), suggesting that these genes contribute to cell wall organization. A triple mutant lacking UTR2, CRH11, and CRH12 produced a defective cell wall, as inferred from increased sensitivity to cell wall-degrading enzymes, decreased ability of protoplasts to regenerate a new wall, constitutive activation of Mkc1p, the mitogen-activated protein kinase of the cell wall integrity pathway, and an increased chitin content of the cell wall. Importantly, this was accompanied by a decrease in alkali-insoluble 1,3--glucan but not total glucan content, suggesting that formation of the linkage between 1,3--glucan and chitin might be affected. In support of this idea, localization of a Utr2p-GFP fusion protein largely coincided with areas of chitin incorporation in C. albicans.As UTR2 and CRH11 expression is regulated by calcineurin, a serine/threonine protein phosphatase involved in tolerance to antifungal drugs, cell wall morphogenesis, and virulence, this points to a possible relationship between calcineurin and the CRH family. Deletion of UTR2, CRH11, and CRH12 resulted in only a partial overlap with calcineurin-dependent phenotypes, suggesting that calcineurin has additional targets. Interestingly, cells deleted for UTR2, CRH11, and CRH12 were, like a calcineurin mutant, avirulent in a mouse model of systemic infection but retained the capacity to colonize target organs (kidneys) as the wild type. In conclusion, this work establishes the role of UTR2, CRH11, and CRH12 in cell wall organization and integrity.

Received for publication, July 5, 2006 , and in revised form, October 23, 2006.

^* This work was supported by a Howard Hughes Medical Institute grant (to D. S.) as an International Research Scholar and by a grant from the European Union (FUNGWALL) (to F. K). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures, Tables I-III, Fig. 1, and Refs. 1-6.

¹ Present address: Biomerieux Italia, via Fiume Bianco 56, 00144 Roma, Italy.

² To whom correspondence should be addressed. Tel.: 41-21-3144083; Fax: 41-21-3144060; E-mail: Dominique.Sanglard{at}chuv.ch.

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