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J. Biol. Chem., Vol. 283, Issue 15, 9724-9736, April 11, 2008

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Identification of a New Family of Genes Involved in β-1,2-Mannosylation of Glycans in Pichia pastoris and Candida albicans^*

Céline Mille¹, Piotr Bobrowicz¹, Pierre-André Trinel, Huijuan Li, Emmanuel Maes^¶, Yann Guerardel^¶, Chantal Fradin, María Martínez-Esparza^||, Robert C. Davidson, Guilhem Janbon^**, Daniel Poulain², and Stefan Wildt

From the Unité de Physiopathologie des Candidoses, INSERM U799, Université de Lille 2 EA 2684, Lille 59045, France, Strain Development, GlycoFi, Inc./Merck & Co., Inc., Lebanon, New Hampshire 03766, ^¶Unité de Glycobiologie Structurale et Fonctionnelle, UMR CNRS 8576, Villeneuve d'Ascq 59655, France, the ^||Department of Biochemistry, Molecular Biology (B) and Immunology, Medical School, University of Murcia, Murcia 30100, Spain, and ^**Unité de Mycologie Moléculaire, Institut Pasteur, Paris 75015, France

Structural studies of cell wall components of the pathogenic yeast Candida albicans have demonstrated the presence of β-1,2-linked oligomannosides in phosphopeptidomannan and phospholipomannan. During C. albicans infection, β-1,2-oligomannosides play an important role in host/pathogen interactions by acting as adhesins and by interfering with the host immune response. Despite the importance of β-1,2-oligomannosides, the genes responsible for their synthesis have not been identified. The main reason is that the reference species Saccharomyces cerevisiae does not synthesize β-linked mannoses. On the other hand, the presence of β-1,2-oligomannosides has been reported in the cell wall of the more genetically tractable C. albicans relative, P. pastoris. Here we present the identification, cloning, and characterization of a novel family of fungal genes involved in β-mannose transfer. Employing in silico analysis, we identified a family of four related new genes in P. pastoris and subsequently nine homologs in C. albicans. Biochemical, immunological, and structural analyses following deletion of four genes in P. pastoris and deletion of four genes acting specifically on C. albicans mannan demonstrated the involvement of these new genes in β-1,2-oligomannoside synthesis. Phenotypic characterization of the strains deleted in β-mannosyltransferase genes (BMTs) allowed us to describe the stepwise activity of Bmtps and acceptor specificity. For C. albicans, despite structural similarities between mannan and phospholipomannan, phospholipomannan β-mannosylation was not affected by any of the CaBMT1–4 deletions. Surprisingly, depletion in mannan major β-1,2-oligomannoside epitopes had little impact on cell wall surface β-1,2-oligomannoside antigenic expression.

Received for publication, October 25, 2007 , and in revised form, January 30, 2008.

^* This work was supported in part by the European Programme Interreg IIIA. 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Inserm U799, Lille 59045, France. Tel.: 33-3-20-62-34-20; Fax: 33-3-20-62-34-16; E-mail: dpoulain{at}univ-lille2.fr.

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