Adhesins in Human Fungal Pathogens: Glue with Plenty of Stick

Groot, Piet W. J. de; Bader, Oliver; Boer, A. De; Weig, Michael; Chauhan, Neeraj

doi:10.1128/ec.00364-12

Cited by 250 publications

(306 citation statements)

References 124 publications

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“…1; also see Fig. S6) (7,12,30). Additionally, C. albicans and other pathogenic fungi in abscesses in human tissue also display surface amyloids (31, 32, and T. Lundberg, M. C. Garcia-Sherman, R. E. Sobonya, P. N. Lipke, and S. A. Klotz, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

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Role of Force-Sensitive Amyloid-Like Interactions in Fungal Catch Bonding and Biofilms

Chan

Lipke

2014

Eukaryot Cell

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The Candida albicans Als adhesin Als5p has an amyloid-forming sequence that is required for aggregation and formation of model biofilms on polystyrene. Because amyloid formation can be triggered by force, we investigated whether laminar flow could activate amyloid formation and increase binding to surfaces. Shearing Saccharomyces cerevisiae cells expressing Als5p or C. albicans at 0.8 dyne/cm 2 increased the quantity and strength of cell-to-surface and cell-to-cell binding compared to that at 0.02 dyne/cm 2 . Thioflavin T fluorescence showed that the laminar flow also induced adhesin aggregation into surface amyloid nanodomains in Als5p Biofilms are communities of microorganisms that form on surfaces. They are ubiquitous and exist in locations as diverse as the mouth, on indwelling catheters, and in fast-moving streams (1-3). Biofilms influence the spread of infections and can clog medical tubing. In the formation of biofilms, adherence of microbes to a surface is followed by cell division and/or capture of free-flowing microbes into the growing biofilm and production of an extracellular matrix of macromolecules. There are functional amyloids present in biofilms made by bacteria and yeast (4-7). These functional amyloids play roles in cell adhesion and in biofilm matrices (4,5,8).In yeasts, adherence to substrate and cell-to-cell aggregation is mediated by cell surface glycoprotein adhesins. The Candida albicans Als adhesins and the Saccharomyces cerevisiae Flo flocculins are examples of adhesins that have little or no homology, but they have similar architecture. Each has an N-terminal secretion signal sequence, a globular ligand-binding region, a midregion containing threonine-rich tandem repeats (which are not homologous between the proteins), a long Ser/Thr-rich glycosylated stalk, and a C-terminal glycosylphosphatidylinositol (GPI) anchor (9). During cell wall biogenesis, the GPI anchor is cleaved in the glycan, and the remnant covalently attaches to cell wall polysaccharide (10). Within the midregions of Als5p, Flo1p, and Flo11p are 6-to 7-amino-acid sequences predicted by TANGO to form amyloids (http://tango.crg.es/) (11, 12). The amyloid sequence in Als5p is important for cell-to-cell aggregation and cell-to-substrate adhesion (7). A single-site amino acid substitution in the amyloid region of Als5p V326N decreases in vitro cell-to-cell aggregation, cellto-substrate adhesion, and fluorescence of the amyloid-reporting dye thioflavin T (ThT) (7). Results with cells expressing the S. cerevisiae flocculins Flo1p and Flo11p are consistent with this model: anti-amyloid dyes Congo red (CR) and thioflavin S (ThS) decrease the rate and extent of flocculation of cells expressing either flocculin (12).Tensile forces present in the environment often increase the strength of bonds formed between microbes, between microbes and surfaces, and between leukocytes and endothelia. These strengthened bonds, called "catch bonds," result in enhanced interactions (13-15). Cell adhesion proteins, such as mammalian selectins and...

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Section: Discussionmentioning

confidence: 99%

“…Additionally, C. albicans and other pathogenic fungi in abscesses in human tissue also display surface amyloids (31, 32, and T. Lundberg, M. C. Garcia-Sherman, R. E. Sobonya, P. N. Lipke, and S. A. Klotz, unpublished data). Thus, the activation by force appears to be a conserved mechanism for fungal adhesins (9,12,30).…”

Section: Discussionmentioning

confidence: 99%

Role of Force-Sensitive Amyloid-Like Interactions in Fungal Catch Bonding and Biofilms

Chan

Lipke

2014

Eukaryot Cell

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“…Similar to S. cerevisiae (48,49), SUMOylation appears to be involved in the regulation of the telomere position effect in C. glabrata. Adherence to the host tissue, an important virulence attribute of C. glabrata, is mediated by a large family of cell wall proteins, including Epa adhesins (30,40). The majority of the adhesin-encoding EPA genes in C. glabrata are transcriptionally silenced due to their close proximity to telomeres (40 -42).…”

Section: Discussionmentioning

confidence: 99%

Identification of Components of the SUMOylation Machinery in Candida glabrata

Gujjula

Veeraiah

Kumar

et al. 2016

Journal of Biological Chemistry

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Regulation of protein function by reversible post-translational modification, SUMOylation, is widely conserved in the eukaryotic kingdom. SUMOylation is essential for cell growth, division, and adaptation to stress in most organisms, including fungi. As these are key factors in determination of fungal virulence, in this study, we have investigated the importance of SUMOylation in the human pathogen, Candida glabrata. We identified the enzymes involved in small ubiquitin-like modifier conjugation and show that there is strong conservation between Saccharomyces cerevisiae and C. glabrata. We demonstrate that SUMOylation is an essential process and that adaptation to stress involves changes in global SUMOylation in C. glabrata. Importantly, loss of the deSUMOylating enzyme CgUlp2 leads to highly reduced small ubiquitin-like modifier protein levels, and impaired growth, sensitivity to multiple stress conditions, reduced adherence to epithelial cells, and poor colonization of specific tissues in mice. Our study thus demonstrates a key role for protein SUMOylation in the life cycle and pathobiology of C. glabrata. SUMOylation, the covalent reversible conjugation of small ubiquitin-like modifier (SUMO) 5 polypeptide to lysine residues, often within the canonical consensus motif ⌿KXE (⌿ and X represent a hydrophobic amino acid and any amino acid, respectively) in target proteins, is a post-translational modification that plays a key regulatory role in several cellular processes, including transcription, protein homeostasis, stress response, and development (1, 2). The process of SUMO attachment consists of the following four steps: (i) processing of the ϳ10-kDa precursor SUMO peptide by SUMO-specific proteases to reveal a C-terminal diglycine motif in the mature SUMO; (ii) ATP-dependent activation of the processed SUMO through the thioester bond formation between the C-terminal glycine of SUMO and the catalytic cysteine of the E1-activating enzyme; (iii) transfer of the SUMO polypeptide from the E1 enzyme to a conserved cysteine in the E2-conjugating enzyme via a thioester linkage; and (iv) E3 ligase-mediated formation of an isopeptide bond between the C-terminal glycine of the SUMO and the ⑀-amino group of the lysine residue within the conserved sequence on the target protein (2, 3). Besides the precursor SUMO maturation, the SUMO-specific peptidases are also able to hydrolyze the isopeptide bond between SUMO and SUMO-modified proteins thereby rendering the SUMOylation process reversible.The SUMO polypeptide is ubiquitously present in all eukaryotes and highly conserved from yeast to mammals (1-3). SUMO modification of protein substrates has diverse functional consequences and range from increased protein stability to altered subcellular localization (1-3). Furthermore, deregulated expression of SUMOylation components has been implicated in several human diseases, including neurodegeneration, heart failure, cancer, diabetes, and infections by bacterial and viral pathogens (4, 5).In the yeast Saccharomyces cerevisiae,...

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“…The wall proteome also reflects morphotype and contains yeast-and hypha-specific wall proteins (50). In addition, the wall proteome is involved in controlling cell wall porosity and cell adhesiveness and hydrophobicity, n recognizing specific substrates, and in forming biofilms (11,16,17,39,49,51).…”

Section: Quantitative Analysis Of the Cell Walls Of S Cerevisiae Andmentioning

confidence: 99%

Cell Wall-Related Bionumbers and Bioestimates of Saccharomyces cerevisiae and Candida albicans

2014

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Bionumbers and bioestimates are valuable tools in biological research. Here we focus on cell wall-related bionumbers and bioestimates of the budding yeast Saccharomyces cerevisiae and the polymorphic, pathogenic fungus Candida albicans. We discuss the linear relationship between cell size and cell ploidy, the correlation between cell size and specific growth rate, the effect of turgor pressure on cell size, and the reason why using fixed cells for measuring cellular dimensions can result in serious underestimation of in vivo values. We further consider the evidence that individual buds and hyphae grow linearly and that exponential growth of the population results from regular formation of new daughter cells and regular hyphal branching. Our calculations show that hyphal growth allows C. albicans to cover much larger distances per unit of time than the yeast mode of growth and that this is accompanied by strongly increased surface expansion rates. We therefore predict that the transcript levels of genes involved in wall formation increase during hyphal growth. Interestingly, wall proteins and polysaccharides seem barely, if at all, subject to turnover and replacement. A general lesson is how strongly most bionumbers and bioestimates depend on environmental conditions and genetic background, thus reemphasizing the importance of well-defined and carefully chosen culture conditions and experimental approaches. Finally, we propose that the numbers and estimates described here offer a solid starting point for similar studies of other cell compartments and other yeast species.

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Adhesins in Human Fungal Pathogens: Glue with Plenty of Stick

Cited by 250 publications

References 124 publications

Role of Force-Sensitive Amyloid-Like Interactions in Fungal Catch Bonding and Biofilms

Role of Force-Sensitive Amyloid-Like Interactions in Fungal Catch Bonding and Biofilms

Identification of Components of the SUMOylation Machinery in Candida glabrata

Cell Wall-Related Bionumbers and Bioestimates of Saccharomyces cerevisiae and Candida albicans

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