Complete glycosylphosphatidylinositol anchors are required in <i>Candida albicans</i> for full morphogenesis, virulence and resistance to macrophages

Richard, Mathias L.; Ibata-Ombetta, Stella; Dromer, Françoise; Bordon-Pallier, Florence; Jouault, Thierry; Gaillardin, Claude

doi:10.1046/j.1365-2958.2002.02926.x

Cited by 77 publications

(79 citation statements)

References 46 publications

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“…Our results with CaGPI19 suggest that single-allele disruption of CaGPI19 is not enough to affect azole susceptibilities and it is only when levels are greatly depleted that sensitivity to azoles is noticed, thus confirming a dosage-dependency of this gene. CaGPI7 mutants do not show any difference in response to either amphotericin B or azoles (Richard et al, 2002), though it should be noted that this gene is not essential and its product is responsible for a GPI-modifying, rather than synthetic, activity. Thus, while the data suggest a specific interaction of GPI-GnT with ergosterol biosynthesis, we do not discount the possibility that perturbation of other GPI biosynthetic enzymes may also affect azole sensitivities.…”

Section: Discussionmentioning

confidence: 93%

“…Surprisingly, on solid medium, we were unable to detect any sensitivity to CFW at all the concentrations tested (up to lethal concentrations). This is quite unlike the deletion of CaSMP3 and GPI7, which, though further downstream in the GPI biosynthetic pathway, show a marked sensitivity to CFW (Grimme et al, 2004;Richard et al, 2002). The reason for this difference is not clear, though it may be noted that deletions of different GPI-anchored proteins did not have the same effect on cell wall chitin (Plaine et al, 2008).…”

Section: Discussionmentioning

confidence: 98%

“…Homologues of all proteins, except DPM2, have also been identified in members of the genus Saccharomyces (Vossen et al, 1995;Leidich et al, 1995;Leidich & Orlean, 1996;Yan et al, 2001). In C. albicans, very few studies have been carried out on the GPI anchor biosynthetic pathway itself and these have been restricted to genes further downstream in the pathway, for example CaSMP3 and Candida GPI7/LAS2 (Grimme et al, 2004;Richard et al, 2002). To our knowledge, no study to date has focused on the C. albicans GPI-GnT complex.…”

Section: Introductionmentioning

confidence: 99%

“…The major difficulty with studying components of the first complex of the pathway in Candida is that intact microsomes from this organism appear to be inactive, unlike those from yeast and human cell lines, removing any chance of a direct assay. However, studies on CaSmp3p and Gpi7p have shown that loss of these proteins causes reduced growth (Grimme et al, 2004) and virulence, as measured by the inability of the mutants to form hyphae, and their reduced virulence in mice (Richard et al, 2002). This paper focuses on one subunit of the Candida GPI-GnT complex, CaGPI19.…”

Section: Introductionmentioning

confidence: 99%

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The Candida albicans homologue of PIG-P, CaGpi19p: gene dosage and role in growth and filamentation

2010

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Glycosylphosphatidyl inositol (GPI)-anchored proteins in Candida albicans are responsible for a vast range of functions, and deletions in certain GPI-anchored proteins severely reduce adhesion and virulence of this organism. In addition, completely modified GPIs are necessary for virulence. GPI anchor biosynthesis is essential for viability and starts with the transfer of N-acetylglucosamine to phosphatidylinositol. This step is catalysed by a multi-subunit complex, GPI–N-acetylglucosaminyltransferase (GPI–GnT). In this, the first report to our knowledge on a subunit of the Candida GPI–GnT complex, we show that CaGpi19p is the functional equivalent of the Saccharomyces cerevisiae Gpi19p. An N-terminal truncation mutant of CaGpi19p functionally complements a conditionally lethal S. cerevisiae gpi19 mutant. Further, we constructed a conditional null mutant of CaGPI19 by disrupting one allele and placing the remaining copy under the control of the MET3 promoter. Repression leads to growth defects, cell wall biogenesis aberrations, azole sensitivity and hyperfilamention. In addition, there is a noticeable gene dosage effect, with the heterozygote also displaying intermediate degrees of most phenotypes. The mutants also displayed a reduced susceptibility to the antifungal agent amphotericin B. Collectively, the results suggest that CaGPI19 is required for normal morphology and cell wall architecture.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Candida albicans homologue of PIG-P, CaGpi19p: gene dosage and role in growth and filamentation

2010

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“…The presence of a GPI anchor has been demonstrated in cell-wall proteins of different fungal species (Frieman et al, 2002;Moukadiri et al, 1997;Staab et al, 1999;Wojciechowicz et al, 1993). The presence of the GPI anchor seems to play an important role in the biology of C. albicans, as mutants are affected in morphogenesis, virulence and cell-wall composition (Richard et al, 2002). The total number of glucanase-extractable mannoproteins identified in C. albicans so far is small, but it is likely that this number will increase in the very near future as a result of homology studies following BLAST searches in the genome database of this fungus.…”

Section: Introductionmentioning

confidence: 99%

Identification and study of a Candida albicans protein homologous to Saccharomyces cerevisiae Ssr1p, an internal cell-wall protein

et al. 2003

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After screening of a Candida albicans genome database, the product of an ORF (IPF 3054) that has 62 % homology with Saccharomyces cerevisiae Ssr1p, an internal cell-wall protein, was identified and named CaSsr1p. The deduced amino acid sequence shows that CaSsr1p contains an N-terminal hydrophobic signal peptide, is rich in Ser and Thr amino acids and has a potential glycosylphosphatidylinositol-attachment signal. CaSsr1p is released following degradation of isolated cell walls by zymolyase (mainly a 1,3-b-glucanase) and therefore seems to be covalently linked to the b-glucan of the cell walls. Both disruption and overexpression of the CaSSR1 gene caused an increased sensitivity to calcofluor white, Congo red and zymolyase digestion. These results suggest that CaSsr1p has a structural role associated with the cell-wall b-glucan. INTRODUCTIONCandida albicans is an opportunistic pathogenic fungus in humans which can cause either septicaemic or mucosal infections (Odds, 1988(Odds, , 1994. The number of fungal infections caused by C. albicans has increased dramatically in the last few decades, due to the rise in the number of immunocompromised patients and their life expectancies (Fox, 1993). C. albicans is a dimorphic organism capable of reproducing by budding (yeast cells) or by producing germ tubes (mycelial cells) depending upon environmental factors (Odds, 1988); this morphological transition has been associated with pathogenicity (Calderone & Braun, 1991;Odds, 1988;Sentandreu et al., 1993). Because the cell wall of C. albicans is the fungal structure responsible for the initial interaction with the host and for the characteristic shape of each growth form, several studies have focused on its biosynthesis and function (Gozalbo et al., 1994;Sentandreu et al., 1993;Valentin et al., 2000).The cell wall of C. albicans is a complex biochemical entity composed mainly of three components, namely, glucans (1,3-b-and 1,6-b-glucan), mannoproteins and chitin (Fleet, 1991;Valentin et al., 2000). The b-glucans are the main components, accounting for 50-60 % by weight of the cell wall in C. albicans and other fungi. Chitin, a linear polymer of 1,4-b-linked N-acetylglucosamine units, is a relatively minor (1-10 %) but important constituent. In most fungi, b-glucans and chitin polymers account for the rigidity of the cell wall as well as its morphology . Mannoproteins represent 30-40 % of the total cell wall and determine the surface properties, enabling C. albicans cells to interact and adhere to host tissues (Chaffin et al., 1998).Cell-wall mannoproteins can be divided into three groups according to the methods used for their extraction. One group can be solubilized by detergents, such as SDS, or chaotropic agents, such as urea, and is formed by mannoproteins loosely associated with other components of the cell wall (Elorza et al., 1985;Valentin et al., 1984). The second group can be extracted by reducing agents, DTT or b-mercaptoethanol (Casanova et al., 1989;Orlean et al., 1986). The third group can be released from the ce...

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Generating anchors only to lose them: The unusual story of glycosylphosphatidylinositol anchor biosynthesis and remodeling in yeast and fungi

et al. 2018

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Glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) are present ubiquitously at the cell surface in all eukaryotes. They play a crucial role in the interaction of the cell with its external environment, allowing the cell to receive signals, respond to challenges, and mediate adhesion. In yeast and fungi, they also participate in the structural integrity of the cell wall and are often essential for survival. Roughly four decades after the discovery of the first GPI-APs, this review provides an overview of the insights gained from studies of the GPI biosynthetic pathway and the future challenges in the field. In particular, we focus on the biosynthetic pathway in Saccharomyces cerevisiae, which has for long been studied as a model organism. Where available, we also provide information about the GPI biosynthetic steps in other yeast/ fungi. Although the core structure of the GPI anchor is conserved across organisms, several variations are built into the biosynthetic pathway. The present Review specifically highlights these variations and their implications. There is growing evidence to suggest that several phenotypes are common to GPI deficiency and should be expected in GPI biosynthetic mutants. However, it appears that several phenotypes are unique to a specific step in the pathway and may even be species-specific. These could suggest the points at which the GPI biosynthetic pathway intersects with other important cellular pathways and could be points of regulation. They could be of particular significance in the study of pathogenic fungi and in identification of new and specific antifungal drugs/ drug targets. © 2018 IUBMB Life, 70(5):355-383, 2018.

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Complete glycosylphosphatidylinositol anchors are required in Candida albicans for full morphogenesis, virulence and resistance to macrophages

Cited by 77 publications

References 46 publications

The Candida albicans homologue of PIG-P, CaGpi19p: gene dosage and role in growth and filamentation

The Candida albicans homologue of PIG-P, CaGpi19p: gene dosage and role in growth and filamentation

Identification and study of a Candida albicans protein homologous to Saccharomyces cerevisiae Ssr1p, an internal cell-wall protein

Generating anchors only to lose them: The unusual story of glycosylphosphatidylinositol anchor biosynthesis and remodeling in yeast and fungi

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