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J. Biol. Chem., Vol. 279, Issue 46, 47952-47960, November 12, 2004

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Inactivation of CaMIT1 Inhibits Candida albicans Phospholipomannan -Mannosylation, Reduces Virulence, and Alters Cell Wall Protein -Mannosylation^*

Celine Mille, Guilhem Janbon¶, Florence Delplace||, Stella Ibata-Ombetta, Claude Gaillardin**, Gérard Strecker||, Thierry Jouault, Pierre-André Trinel, and Daniel Poulain

From the Laboratoire de Mycologie Fondamentale et Appliquée, Equipe Inserm E0360, Faculté de Médecine, Pôle Recherche, Place de Verdun, 59045 Lille Cedex, ^¶Unité de Mycologie Moléculaire, Institut Pasteur, 28 Rue du Dr Roux, 75015 Paris, ^||Unité de Glycobiologie Structurale et Fonctionnelle, Université des Sciences et Technologies de Lille, Unité Mixte de Recherche 8576 CNRS, 59655 Villeneuve D'Ascq Cedex, and the ^**Laboratoire de Génétique Moléculaire et Cellulaire, Institut National Agronomique Paris-Grignon, 78850 Thiverval-Grignon, France

Studies on Candida albicans phospholipomannan have suggested a novel biosynthetic pathway for yeast glycosphingolipids. This pathway is thought to diverge from the usual pathway at the mannose-inositol-phospho-ceramide (MIPC) step. To confirm this hypothesis, a C. albicans gene homologue for the Saccharomyces cerevisiae SUR1 gene was identified and named MIT1 as it coded for GDP-mannose:inositol-phospho-ceramide mannose transferase. Two copies of this gene were disrupted. Western blots of cell extracts revealed that strain mit1 contained no PLM. Thin layer chromatography and mass spectrometry confirmed that mit1 did not synthesize MIPC, demonstrating a role of MIT1 in the mannosylation of C. albicans IPCs. As MIT1 disruption prevented downstream -1,2 mannosylation, mit1 represents a new C. albicans mutant affected in the expression of these specific virulence attributes, which act as adhesins/immunomodulators. mit1 was less virulent during both the acute and chronic phases of systemic infection in mice (75 and 50% reduction in mortality, respectively). In vitro, mit1 was not able to escape macrophage lysis through down-regulation of the ERK1/2 phosphorylation pathway previously shown to be triggered by PLM. Phenotypic analysis also revealed pleiotropic effects of MIT1 disruption. The most striking observation was a reduced -mannosylation of phosphopeptidomannan. Increased -mannosylation of mannoproteins was observed under growth conditions that prevented the association of -oligomannosides with phosphopeptidomannan, but not with PLM. This suggests that C. albicans has strong regulatory mechanisms associating -oligomannoses with different cell wall carrier molecules. These mechanisms and the impact of the different presentations of -oligomannoses on the host response need to be defined.

Received for publication, May 18, 2004 , and in revised form, September 3, 2004.

^* This work was supported by the Réseau Infection Fongique. The mass spectrometry facility used in this study is funded by the European Community (FEDER), the Région Nord-Pas de Calais (France), the CNRS, and the Université des Sciences et Technologies de Lille. 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.

Supported by a grant from the Fondation pour la Recherche Médicale.

To whom correspondence should be addressed. 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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