Extracellular glycosylphosphatidylinositol-anchored mannoproteins and proteases of<i>Cryptococcus neoformans</i>

Eigenheer, Richard A.; Lee, Young Jin; Blumwald, Eduardo; Phinney, Brett S.; Gelli, Angela C

doi:10.1111/j.1567-1364.2006.00198.x

Cited by 80 publications

(72 citation statements)

References 48 publications

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“…Furthermore, ␤-1,3 glucanase activity has been detected in cryptococcal secretions (34), and four putative endo-␤-1,3 glucanase genes are present in the cryptococcal genome data base (35). The product of one gene (CNBC2400), is present in cryptococcal cell walls (36), and the remaining three are predicted to be GPI-anchored (35). Interestingly, no ␤-1,6 glucanase genes or activity have been found, suggesting that Plb1 is linked via ␤-1,6-linked glucan to ␤-1,3-linked glucan in the central scaffold of the cell wall and that endogenous ␤-1,3 glucanases are responsible for its secretion.…”

Section: Discussionmentioning

confidence: 99%

Cell Wall-linked Cryptococcal Phospholipase B1 Is a Source of Secreted Enzyme and a Determinant of Cell Wall Integrity

Siafakas

Sorrell

Wright

et al. 2007

Journal of Biological Chemistry

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Phospholipase B (Plb1) is secreted by pathogenic fungi and is a proven virulence determinant in Cryptococcus neoformans. Cell-associated Plb1 is presumptively involved in fungal membrane biogenesis and remodelling. We have also identified it in cryptococcal cell walls. Motif scanning programs predict that Plb1 is attached to cryptococcal membranes via a glycosylphosphatidylinositol (GPI) anchor, which could regulate Plb1 export and secretion. A functional GPI anchor was identified in cellassociated Plb1 by (G)PI-specific phospholipase C (PLC)-induced release of Plb1 from strain H99 membrane rafts and inhibition of GPI anchor synthesis by YW3548, which prevented Plb1 secretion and transport to membranes and cell walls. Plb1 containing ␤-1,6-linked glucan was released from H99 (wildtype strain) cell walls by ␤-1,3 glucanase, consistent with covalent attachment of Plb1 via ␤-1,6-linked glucans to ␤-1,3-linked glucan in the central scaffold of the wall. Naturally secreted Plb1 also contained ␤-1,6-linked glucan, confirming that it originated from the cell wall. Plb1 maintains cell wall integrity because a H99 deletion mutant, ⌬PLB1, exhibited a morphological defect and was more susceptible than H99 to cell wall disruption by SDS and Congo red. Growth of ⌬PLB1 was unaffected by caffeine, excluding an effect of Plb1 on cell wall biogenesis-related signaling pathways. Environmental (heat) stress caused Plb1 accumulation in cell walls, with loss from membranes and reduced secretion, further supporting the importance of Plb1 in cell wall integrity. This is the first demonstration that Plb1 contributes to fungal survival by maintaining cell wall integrity and that the cell wall is a source of secreted enzyme.

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Section: Discussionmentioning

confidence: 99%

Cell Wall-linked Cryptococcal Phospholipase B1 Is a Source of Secreted Enzyme and a Determinant of Cell Wall Integrity

Siafakas

Sorrell

Wright

et al. 2007

Journal of Biological Chemistry

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“…Studies by Baker et al (2) have identified three chitin deacetylases (Cda1, Cda2, and Cda3) in C. neoformans that are responsible for total chitosan production during vegetative growth. These enzymes are proteins that have been localized to the cell wall, most likely through a glycosylphosphatidylinositol anchor remnant (15). It is not known if the chitin is converted to chitosan by the chitin deacetylases while they are covalently attached to the wall or if the deacetylation occurs at an earlier step prior to the chitin deacetylases being linked to the wall.…”

Section: Discussionmentioning

confidence: 99%

PKC1 Is Essential for Protection against both Oxidative and Nitrosative Stresses, Cell Integrity, and Normal Manifestation of Virulence Factors in the Pathogenic Fungus Cryptococcus neoformans

Gerik¹,

Bhimireddy²,

Ryerse³

et al. 2008

Eukaryot Cell

103

155

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Cell wall integrity is crucial for fungal growth, survival, and pathogenesis. Responses to environmental stresses are mediated by the highly conserved Pkc1 protein and its downstream components. In this study, we demonstrate that both oxidative and nitrosative stresses activate the PKC1 cell integrity pathway in wild-type cells, as measured by phosphorylation of Mpk1, the terminal protein in the PKC1 phosphorylation cascade. Furthermore, deletion of PKC1 shows that this gene is essential for defense against both oxidative and nitrosative stresses; however, other genes involved directly in the PKC1 pathway are dispensable for protection against these stresses. This suggests that Pkc1 may have multiple and alternative functions other than activating the mitogen-activated protein kinase cascade from a "top-down" approach. Deletion of PKC1 also causes osmotic instability, temperature sensitivity, severe sensitivity to cell wall-inhibiting agents, and alterations in capsule and melanin. Furthermore, the vital cell wall components chitin and its deacetylated form chitosan appear to be mislocalized in a pkc1⌬ strain, although this mutant contains wild-type levels of both of these polymers. These data indicate that loss of Pkc1 has pleiotropic effects because it is central to many functions either dependent on or independent of PKC1 pathway activation. Notably, this is the first time that Pkc1 has been implicated in protection against nitrosative stress in any organism.

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“…A potential impact on secretion was also evident from the increased extracellular protease activity observed for the mfe2⌬ and mfe2⌬ had1⌬ mutants. Proteases could potentially contribute to virulence, and C. neoformans is known to secrete a variety of proteases (6,12). In general, the pleiotropic phenotypes may be due to several possible metabolic perturbations, including the accumulation of intermediates (e.g., acyl-CoA molecules), altered fatty acid availability leading to changes in phospholipid and sterol composition in membranes, and reduced acetyl-CoA production (42).…”

Section: Discussionmentioning

confidence: 99%

Peroxisomal and Mitochondrial β-Oxidation Pathways Influence the Virulence of the Pathogenic Fungus Cryptococcus neoformans

2012

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ABSTRACTAn understanding of the connections between metabolism and elaboration of virulence factors during host colonization by the human-pathogenic fungusCryptococcus neoformansis important for developing antifungal therapies. Lipids are abundant in host tissues, and fungal pathogens in the phylum basidiomycota possess both peroxisomal and mitochondrial β-oxidation pathways to utilize this potential carbon source. In addition, lipids are important signaling molecules in both fungi and mammals. In this report, we demonstrate that defects in the peroxisomal and mitochondrial β-oxidation pathways influence the growth ofC. neoformanson fatty acids as well as the virulence of the fungus in a mouse inhalation model of cryptococcosis. Disease attenuation may be due to the cumulative influence of altered carbon source acquisition or processing, interference with secretion, changes in cell wall integrity, and an observed defect in capsule production for the peroxisomal mutant. Altered capsule elaboration in the context of a β-oxidation defect was unexpected but is particularly important because this trait is a major virulence factor forC. neoformans. Additionally, analysis of mutants in the peroxisomal pathway revealed a growth-promoting activity forC. neoformans, and subsequent work identified oleic acid and biotin as candidates for such factors. Overall, this study reveals that β-oxidation influences virulence inC. neoformansby multiple mechanisms that likely include contributions to carbon source acquisition and virulence factor elaboration.

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Extracellular glycosylphosphatidylinositol-anchored mannoproteins and proteases ofCryptococcus neoformans

Cited by 80 publications

References 48 publications

Cell Wall-linked Cryptococcal Phospholipase B1 Is a Source of Secreted Enzyme and a Determinant of Cell Wall Integrity

Cell Wall-linked Cryptococcal Phospholipase B1 Is a Source of Secreted Enzyme and a Determinant of Cell Wall Integrity

PKC1 Is Essential for Protection against both Oxidative and Nitrosative Stresses, Cell Integrity, and Normal Manifestation of Virulence Factors in the Pathogenic Fungus Cryptococcus neoformans

Peroxisomal and Mitochondrial β-Oxidation Pathways Influence the Virulence of the Pathogenic Fungus Cryptococcus neoformans

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