title: Endoplasmic reticulum alpha-glycosidases of Candida albicans are required for N glycosylation, cell wall integrity, and normal host-fungus interaction.
abstract: 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 Glc(3)Man(9)GlcNAc(2) N-glycan is processed by alpha-glucosidases I and II and alpha1,2-mannosidase to generate Man(8)GlcNAc(2). 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 alpha-glucosidase I, alpha-glucosidase II catalytic subunit, and alpha1,2-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 Cacwh41Delta, Carot2Delta, and Camns1Delta 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 beta-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.
authors.affiliation: Instituto de Investigación en Biología Experimental, Facultad de Química, Universidad de Guanajuato, Apartado Postal 187, Guanajuato, Gto. CP 36000, México.
authors.forename: Héctor M
authors.initials: HM
authors.lastname: Mora-Montes
authors.forename: Steven
authors.initials: S
authors.lastname: Bates
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Diana F
authors.initials: DF
authors.lastname: Díaz-Jiménez
authors.forename: Everardo
authors.initials: E
authors.lastname: López-Romero
authors.forename: Samuel
authors.initials: S
authors.lastname: Zinker
authors.forename: Patricia
authors.initials: P
authors.lastname: Ponce-Noyola
authors.forename: Bart Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.forename: Alistair J P
authors.initials: AJ
authors.lastname: Brown
authors.forename: Frank C
authors.initials: FC
authors.lastname: Odds
authors.forename: Arturo
authors.initials: A
authors.lastname: Flores-Carreón
authors.forename: Neil A R
authors.initials: NA
authors.lastname: Gow
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000201:enzymology*; D002473:Cell Wall / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D005260:Female; D006026:Glycoside Hydrolases / Q000378:metabolism / Q000502:physiology*; D006031:Glycosylation; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D014774:Virulence
chemical_list: D016207:Cytokines; D006026:Glycoside Hydrolases