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Role of the Candida albicans MNN1 gene family in cell wall structure and virulence.

Bates S, Hall RA, Cheetham J, Netea MG, MacCallum DM, Brown AJ, Odds FC, Gow NA - BMC Res Notes (2013)

Bottom Line: However, no gross changes in cell wall composition or N-glycosylation were identified in this mutant, although an extension of phosphomannan chain length was apparent.Although the cell wall defects associated with the mnn14Δ mutant were subtle, this mutant displayed a severe attenuation of virulence in a murine infection model.Mnn14 plays a distinct role from other members of the MNN1 family, demonstrating that specific N-glycan outer chain epitopes are required in the host-pathogen interaction and virulence.

View Article: PubMed Central - HTML - PubMed

Affiliation: College of Life and Environmental Sciences, University of Exeter, Exeter, EX4 4QD, UK. s.bates@ex.ac.uk

ABSTRACT

Background: The Candida albicans cell wall is the first point of contact with the host, and its outer surface is heavily enriched in mannoproteins modified through the addition of N- and O-mannan. Previous work, using mutants with gross defects in glycosylation, has clearly identified the importance of mannan in the host-pathogen interaction, immune recognition and virulence. Here we report the first analysis of the MNN1 gene family, which contains six members predicted to act as α-1,3 mannosyltransferases in the terminal stages of glycosylation.

Findings: We generated single mutants in all members of the C. albicans MNN1 gene family, and disruption of MNN14 led to both in vitro and in vivo defects. Null mutants in other members of the family demonstrated no phenotypic defects, suggesting that these members may display functional redundancy. The mnn14Δ mutant displayed hypersensitivity to agents associated with cell wall and glycosylation defects, suggesting an altered cell wall structure. However, no gross changes in cell wall composition or N-glycosylation were identified in this mutant, although an extension of phosphomannan chain length was apparent. Although the cell wall defects associated with the mnn14Δ mutant were subtle, this mutant displayed a severe attenuation of virulence in a murine infection model.

Conclusion: Mnn14 plays a distinct role from other members of the MNN1 family, demonstrating that specific N-glycan outer chain epitopes are required in the host-pathogen interaction and virulence.

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Phylogram of the C. albicans MNN1 gene family. A multiple sequence alignment and phylogram of the six MNN1 orthologues was generated in Clustal Omega (version 1.1.0).
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Figure 1: Phylogram of the C. albicans MNN1 gene family. A multiple sequence alignment and phylogram of the six MNN1 orthologues was generated in Clustal Omega (version 1.1.0).

Mentions: Our analysis of assembly 21 of the C. albicans genome identified a gene family of 12 members homologous to the S. cerevisiae MNN1/2 family. Similar to S. cerevisiae this family could be divided into two subfamilies based on homology to either MNN1 or MNN2. Six members of the C. albicans MNN1 family were identified (orf19.4279, orf19.4900, orf19.4270, orf19.6996, orf19.753 and orf19.6313) and designated MNN1, MNN12, MNN13, MNN14, MNN15 and MNN16. The proteins encoded by this family share 19-44% homology between members (Table 1, Figure 1) and a characteristic type II membrane protein topology, with a single N-terminal membrane spanning region (17–19 amino acids) preceded by a short (5–13 amino acid) cytosolic tail. All Mnn1 family members, except Mnn16, contain the conserved DxD motif known to be important for substrate and co-factor binding [24], suggesting that Mnn16 may have altered functionality. The MNN1 family shows varying numbers in the sequenced CUG clade species [25] with C. albicans, Candida tropicalis and Candida parapsilosis encoding 6, 8, and 4 members respectively, compared to the non-pathogenic or infrequent pathogens, Lodderomyces elongisporus, Candida guilliermondii, Candida lusitaniae, and Debaryomyces hansenii which have 5, 4, 3 and 3 members respectively.


Role of the Candida albicans MNN1 gene family in cell wall structure and virulence.

Bates S, Hall RA, Cheetham J, Netea MG, MacCallum DM, Brown AJ, Odds FC, Gow NA - BMC Res Notes (2013)

Phylogram of the C. albicans MNN1 gene family. A multiple sequence alignment and phylogram of the six MNN1 orthologues was generated in Clustal Omega (version 1.1.0).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750861&req=5

Figure 1: Phylogram of the C. albicans MNN1 gene family. A multiple sequence alignment and phylogram of the six MNN1 orthologues was generated in Clustal Omega (version 1.1.0).
Mentions: Our analysis of assembly 21 of the C. albicans genome identified a gene family of 12 members homologous to the S. cerevisiae MNN1/2 family. Similar to S. cerevisiae this family could be divided into two subfamilies based on homology to either MNN1 or MNN2. Six members of the C. albicans MNN1 family were identified (orf19.4279, orf19.4900, orf19.4270, orf19.6996, orf19.753 and orf19.6313) and designated MNN1, MNN12, MNN13, MNN14, MNN15 and MNN16. The proteins encoded by this family share 19-44% homology between members (Table 1, Figure 1) and a characteristic type II membrane protein topology, with a single N-terminal membrane spanning region (17–19 amino acids) preceded by a short (5–13 amino acid) cytosolic tail. All Mnn1 family members, except Mnn16, contain the conserved DxD motif known to be important for substrate and co-factor binding [24], suggesting that Mnn16 may have altered functionality. The MNN1 family shows varying numbers in the sequenced CUG clade species [25] with C. albicans, Candida tropicalis and Candida parapsilosis encoding 6, 8, and 4 members respectively, compared to the non-pathogenic or infrequent pathogens, Lodderomyces elongisporus, Candida guilliermondii, Candida lusitaniae, and Debaryomyces hansenii which have 5, 4, 3 and 3 members respectively.

Bottom Line: However, no gross changes in cell wall composition or N-glycosylation were identified in this mutant, although an extension of phosphomannan chain length was apparent.Although the cell wall defects associated with the mnn14Δ mutant were subtle, this mutant displayed a severe attenuation of virulence in a murine infection model.Mnn14 plays a distinct role from other members of the MNN1 family, demonstrating that specific N-glycan outer chain epitopes are required in the host-pathogen interaction and virulence.

View Article: PubMed Central - HTML - PubMed

Affiliation: College of Life and Environmental Sciences, University of Exeter, Exeter, EX4 4QD, UK. s.bates@ex.ac.uk

ABSTRACT

Background: The Candida albicans cell wall is the first point of contact with the host, and its outer surface is heavily enriched in mannoproteins modified through the addition of N- and O-mannan. Previous work, using mutants with gross defects in glycosylation, has clearly identified the importance of mannan in the host-pathogen interaction, immune recognition and virulence. Here we report the first analysis of the MNN1 gene family, which contains six members predicted to act as α-1,3 mannosyltransferases in the terminal stages of glycosylation.

Findings: We generated single mutants in all members of the C. albicans MNN1 gene family, and disruption of MNN14 led to both in vitro and in vivo defects. Null mutants in other members of the family demonstrated no phenotypic defects, suggesting that these members may display functional redundancy. The mnn14Δ mutant displayed hypersensitivity to agents associated with cell wall and glycosylation defects, suggesting an altered cell wall structure. However, no gross changes in cell wall composition or N-glycosylation were identified in this mutant, although an extension of phosphomannan chain length was apparent. Although the cell wall defects associated with the mnn14Δ mutant were subtle, this mutant displayed a severe attenuation of virulence in a murine infection model.

Conclusion: Mnn14 plays a distinct role from other members of the MNN1 family, demonstrating that specific N-glycan outer chain epitopes are required in the host-pathogen interaction and virulence.

Show MeSH
Related in: MedlinePlus