Unraveling Unique Structure and Biosynthesis Pathway of N-Linked Glycans in Human Fungal Pathogen Cryptococcus neoformans by Glycomics Analysis

Park, Jeong Nam; Lee, Dong Jik; Kwon, Ohsuk; Oh, Doo-Byoung; Bahn, Yong-Sun; Kang, Hyun Ah

doi:10.1074/jbc.m112.354209

Cited by 40 publications

(43 citation statements)

References 50 publications

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“…Metabolic imbalance might also explain the slightly increased xylosylation of the mutant capsule polysaccharide. Although xylose is incorporated into cryptococcal glycoproteins (70,71), it is a relatively minor component of the cell wall overall, whereas it plays a major role in capsule polysaccharides. Reduced wall turnover might therefore have a lesser effect on this capsule moiety than on mannose, for example, which is a major component of both structures, leading to the altered ratio of these components that we observed in GXM.…”

Section: Discussionmentioning

confidence: 99%

Pbx Proteins in Cryptococcus neoformans Cell Wall Remodeling and Capsule Assembly

et al. 2014

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The cryptococcal capsule is a critical virulence factor of an important pathogen, but little is known about how it is associated with the cell or released into the environment. Two mutants lacking PBX1 and PBX2 were found to shed reduced amounts of the capsule polysaccharide glucuronoxylomannan (GXM). Nuclear magnetic resonance, composition, and physical analyses showed that the shed material was of normal mass but was slightly enriched in xylose. In contrast to previous reports, this material contained no glucose. Notably, the capsule fibers of pbx⌬ mutant cells grown under capsule-inducing conditions were present at a lower than usual density and were loosely attached to the cell wall. Mutant cell walls were also defective, as indicated by phenotypes including abnormal cell morphology, reduced mating filamentation, and altered cell integrity. All observed phenotypes were shared between the two mutants and exacerbated in a double mutant. Consistent with a role in surface glycan synthesis, the Pbx proteins localized to detergent-resistant membrane domains. These results, together with the sequence motifs in the Pbx proteins, suggest that Pbx1 and Pbx2 are redundant proteins that act in remodeling the cell wall to maintain normal cell morphology and precursor availability for other glycan synthetic processes. Their absence results in aberrant cell wall growth and metabolic imbalance, which together impact cell wall and capsule synthesis, cell morphology, and capsule association. The surface changes also lead to increased engulfment by host phagocytes, consistent with the lack of virulence of pbx mutants in animal models.

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Section: Discussionmentioning

confidence: 99%

Pbx Proteins in Cryptococcus neoformans Cell Wall Remodeling and Capsule Assembly

et al. 2014

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“…The results of our previous study indicated that KTR3, the only member of the KRE2/MNT1 family encoding putative ␣1,2-mannosyltransferases in C. neoformans, is not involved in N-glycosylation but is associated with O-glycan synthesis (28). To characterize the specific roles of KTR3 in O-glycan extension in the Golgi of C. neoformans, we analyzed the O-glycan profiles of the ktr3⌬ mutant and the ktr3⌬/KTR3 reintegrated strains by HPLC.…”

Section: Analysis Of the Glycan Profile Of C Neoformans Ktr3⌬ Mutantmentioning

confidence: 99%

“…However, the structure and biosynthetic pathway of cryptococcal oligosaccharides assembled on mannoproteins have only been partially characterized. We previously reported the unique features of the biosynthetic pathway and the structure of cryptococcal N-linked glycans containing xylose and xylosyl phosphate residues (28). A recent report by Reilly et al (29) showed that C. neoformans O-linked glycans mostly consist of 1-4 mannose residues, whereas minor species contain xylose and xylosyl phosphate residues.…”

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confidence: 95%

Unraveling the Novel Structure and Biosynthetic Pathway of O-Linked Glycans in the Golgi Apparatus of the Human Pathogenic Yeast Cryptococcus neoformans

Lee¹,

Bahn

Kim

et al. 2015

Journal of Biological Chemistry

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Background: Information on the structure of cryptococcal O-glycans is limited. Results: C. neoformans O-glycans are short manno-oligosaccharides, extended mostly by ␣1,2-linkages but containing an ␣1,6-linkage. Conclusion: Ktr3p adds a second ␣1,2-linked mannnose to major O-glycans, whereas Hoc1p and Hoc3p transfer a third ␣1,6-linked mannose residue to O-glycans with and without xylose, respectively. Significance: This work reports novel features of the cryptococcal O-glycan biosynthesis pathway.

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“…Mammals typically process this initial structure to forms with only three mannose residues, elaborating the modified core with other moieties such as galactose, N-acetylglucosamine, and N-acetylneuraminic acid in the Golgi apparatus (1). In contrast, yeasts maintain most or all of the initial mannose-rich structure and frequently elaborate it to various extents with additional mannose residues, ranging from the relatively limited elongation seen in C. neoformans to the extensive modifications observed in Saccharomyces cerevisiae (2,3). As another example, mammalian O-glycans typically contain fucose, xylose, and N-acetylglucosamine (1).…”

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confidence: 99%

“…Pathogenic members of the Cryptococcus genus have historically been classified by seroreactivity of their capsule polysaccharides (28); serotypes A and D are the main ones responsible for opportunistic infections. The glycoconjugates of C. neoformans include mannose-containing glycoproteins and glycolipids (3,4,29,30). Mannose is also a major component of this organism's extensive polysaccharide capsule (31), which is essential for fungal virulence.…”

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Cryptococcus neoformans Dual GDP-Mannose Transporters and Their Role in Biology and Virulence

et al. 2014

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dCryptococcus neoformans is an opportunistic yeast responsible for lethal meningoencephalitis in humans. This pathogen elaborates a polysaccharide capsule, which is its major virulence factor. Mannose constitutes over one-half of the capsule mass and is also extensively utilized in cell wall synthesis and in glycosylation of proteins and lipids. The activated mannose donor for most biosynthetic reactions, GDP-mannose, is made in the cytosol, although it is primarily consumed in secretory organelles. This compartmentalization necessitates specific transmembrane transporters to make the donor available for glycan synthesis. We previously identified two cryptococcal GDP-mannose transporters, Gmt1 and Gmt2. Biochemical studies of each protein expressed in Saccharomyces cerevisiae showed that both are functional, with similar kinetics and substrate specificities in vitro. We have now examined these proteins in vivo and demonstrate that cells lacking Gmt1 show significant phenotypic differences from those lacking Gmt2 in terms of growth, colony morphology, protein glycosylation, and capsule phenotypes. Some of these observations may be explained by differential expression of the two genes, but others suggest that the two proteins play overlapping but nonidentical roles in cryptococcal biology. Furthermore, gmt1 gmt2 double mutant cells, which are unexpectedly viable, exhibit severe defects in capsule synthesis and protein glycosylation and are avirulent in mouse models of cryptococcosis.

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Unraveling Unique Structure and Biosynthesis Pathway of N-Linked Glycans in Human Fungal Pathogen Cryptococcus neoformans by Glycomics Analysis

Cited by 40 publications

References 50 publications

Pbx Proteins in Cryptococcus neoformans Cell Wall Remodeling and Capsule Assembly

Pbx Proteins in Cryptococcus neoformans Cell Wall Remodeling and Capsule Assembly

Unraveling the Novel Structure and Biosynthetic Pathway of O-Linked Glycans in the Golgi Apparatus of the Human Pathogenic Yeast Cryptococcus neoformans

Cryptococcus neoformans Dual GDP-Mannose Transporters and Their Role in Biology and Virulence

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