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Endoplasmic Reticulum -Glycosidases of Candida albicans Are Required for N Glycosylation, Cell Wall Integrity, and Normal Host-Fungus Interaction

Héctor M. Mora-Montes,^1, Steven Bates,^2, Mihai G. Netea,³ Diana F. Díaz-Jiménez,¹ Everardo López-Romero,¹ Samuel Zinker,⁴ Patricia Ponce-Noyola,¹ Bart Jan Kullberg,³ Alistair J. P. Brown,² Frank C. Odds,² Arturo Flores-Carreón,¹ and Neil A. R. Gow^2*

Instituto de Investigación en Biología Experimental, Facultad de Química, Universidad de Guanajuato, Apartado Postal 187, Guanajuato, Gto. CP 36000, México,¹ School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom,² Department of Medicine, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands,³ Departamento de Genética y Biología Molecular, CINVESTAV del IPN, Apartado Postal 14-740, México, DF 07000, México⁴

Received 11 July 2007/ Accepted 27 September 2007

The cell surface of Candida albicans is enriched in highly glycosylated mannoproteins that are involved in the interaction with the host tissues. N glycosylation is a posttranslational modification that is initiated in the endoplasmic reticulum (ER), where the Glc₃Man₉GlcNAc₂ N-glycan is processed by -glucosidases I and II and 1,2-mannosidase to generate Man₈GlcNAc₂. This N-oligosaccharide is then elaborated in the Golgi to form N-glycans with highly branched outer chains rich in mannose. In Saccharomyces cerevisiae, CWH41, ROT2, and MNS1 encode for -glucosidase I, -glucosidase II catalytic subunit, and 1,2-mannosidase, respectively. We disrupted the C. albicans CWH41, ROT2, and MNS1 homologs to determine the importance of N-oligosaccharide processing on the N-glycan outer-chain elongation and the host-fungus interaction. Yeast cells of Cacwh41, Carot2, and Camns1 null mutants tended to aggregate, displayed reduced growth rates, had a lower content of cell wall phosphomannan and other changes in cell wall composition, underglycosylated β-N-acetylhexosaminidase, and had a constitutively activated PKC-Mkc1 cell wall integrity pathway. They were also attenuated in virulence in a murine model of systemic infection and stimulated an altered pro- and anti-inflammatory cytokine profile from human monocytes. Therefore, N-oligosaccharide processing by ER glycosidases is required for cell wall integrity and for host-fungus interactions.

Published ahead of print on 12 October 2007.

Present address: School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom.

Present address: School of Biosciences, University of Exeter, Exeter EX4 4PS, United Kingdom.