A family of secreted pathogenesis‐related proteins in <i><scp>C</scp>andida albicans</i>

Röhm, Marc; Lindemann, Elena; Hiller, Ekkehard; Ermert, David; Lemuth, Karin; Trkulja, D.; Sogukpinar, O.; Brunner, Herwig; Rupp, Steffen; Urban, Constantin F.; Sohn, Kai

doi:10.1111/mmi.12087

Cited by 30 publications

(37 citation statements)

References 68 publications

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“…C. albicans ECE1 (extent of cell elongation) is highly expressed by hyphae during epithelial infection (Extended Data Fig. 1a,b) and is predicted to encode a secreted protein16. To probe its function we generated a panel of C. albicans ECE1 mutants (Extended Data Table 2).…”

Section: Ece1p Is Critical For Epithelial Activation and Damagementioning

confidence: 99%

Candidalysin is a fungal peptide toxin critical for mucosal infection

Moyes

Wilson

Richardson

et al. 2016

Nature

640

848

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Cytolytic proteins and peptide toxins are classical virulence factors of several bacterial pathogens which disrupt epithelial barrier function, damage cells and activate or modulate host immune responses. Until now human pathogenic fungi were not known to possess such toxins. Here we identify the first fungal cytolytic peptide toxin in the opportunistic pathogen Candida albicans. This secreted toxin directly damages epithelial membranes, triggers a danger response signaling pathway and activates epithelial immunity. Toxin-mediated membrane permeabilization is enhanced by a positively charged C-terminus and triggers an inward current concomitant with calcium influx. C. albicans strains lacking this toxin do not activate or damage epithelial cells and are avirulent in animal models of mucosal infection. We propose the name ‘Candidalysin’ for this cytolytic peptide toxin; a newly identified, critical molecular determinant of epithelial damage and host recognition of the clinically important fungus, C. albicans.

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Section: Ece1p Is Critical For Epithelial Activation and Damagementioning

confidence: 99%

Candidalysin is a fungal peptide toxin critical for mucosal infection

Moyes

Wilson

Richardson

et al. 2016

Nature

640

848

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“…1, Northern analysis was performed to examine the expression of four evolutionarily conserved (as defined using the SYNERGY algorithm [51; http://www.broadinstitute.org/regev/orthogroups/]) C. albicans filament-specific target genes in C. tropicalis, C. parapsilosis, and C. guilliermondii under both filament-inducing and noninducing conditions. HGC1 encodes a G 1 cyclin-related protein important for hyphal development (52), PHR1 encodes a putative cell wall glycosidase important for virulence (53,54), RBT4 encodes a secreted plant pathogenesis-related (PR) protein also associated with virulence (55,56), and CDC12 encodes a septin involved in hyphal growth (57). All of these genes have previously been shown to be significantly induced in response to filamentinducing conditions in C. albicans, including growth in serum at 37°C (50,52,(58)(59)(60).…”

Section: Aliquots Of Cells Grown Formentioning

confidence: 99%

Comparative Evolution of Morphological Regulatory Functions in Candida Species

et al. 2013

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Morphological transitions play an important role in virulence and virulence-related processes in a wide variety of pathogenic fungi, including the most commonly isolated human fungal pathogen Candida albicans. While environmental signals, transcriptional regulators, and target genes associated with C. albicans morphogenesis are well-characterized, considerably little is known about morphological regulatory mechanisms and the extent to which they are evolutionarily conserved in less pathogenic and less filamentous non-albicans Candida species (NACS). We have identified specific optimal filament-inducing conditions for three NACS (C. tropicalis, C. parapsilosis, and C. guilliermondii), which are very limited, suggesting that these species may be adapted for niche-specific filamentation in the host. Only a subset of evolutionarily conserved C. albicans filament-specific target genes were induced upon filamentation in C. tropicalis, C. parapsilosis, and C. guilliermondii. One of the genes showing conserved expression was UME6, a key filament-specific regulator of C. albicans hyphal development. Constitutive high-level expression of UME6 was sufficient to drive increased filamentation as well as biofilm formation and partly restore conserved filament-specific gene expression in both C. tropicalis and C. parapsilosis, suggesting that evolutionary differences in filamentation ability among pathogenic Candida species may be partially attributed to alterations in the expression level of a conserved filamentous growth machinery. In contrast to UME6, NRG1, an important repressor of C. albicans filamentation, showed only a partly conserved role in controlling NACS filamentation. Overall, our results suggest that C. albicans morphological regulatory functions are partially conserved in NACS and have evolved to respond to more specific sets of host environmental cues.

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“…For a detailed protocol, see the study by Röhm et al (24). Excision of the cassette was achieved by incubation in yeast-peptone maltose liquid media (YPM; 1% yeast extract, 2% Bacto peptone, 2% maltose) at 30°C for 24 h. Approximately 300 cells were spread for selection on YPD containing 12.5 g of nourseothricin ml…”

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confidence: 99%

An Expanded Genetic Code in Candida albicans To Study Protein-Protein Interactions In Vivo

et al. 2013

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cFor novel insights into the pathogenicity of Candida albicans, studies on molecular interactions of central virulence factors are crucial. Since methods for the analysis of direct molecular interactions of proteins in vivo are scarce, we expanded the genetic code of C. albicans with the synthetic photo-cross-linking amino acid p-azido-L-phenylalanine (AzF). Interacting molecules in close proximity of this unnatural amino acid can be covalently linked by UV-induced photo-cross-link, which makes unknown interacting molecules available for downstream identification. Therefore, we applied an aminoacyltRNA synthetase and a suppressor tRNA pair (EcTyrtRNA CUA ) derived from Escherichia coli, which was previously reported to be orthogonal in Saccharomyces cerevisiae. We further optimized the aminoacyl-tRNA synthetase for AzF (AzF-RS) and EcTyrtRNA CUA for C. albicans and identified one AzF-RS with highest charging efficiency. Accordingly, incorporation of AzF into selected model proteins such as Tsa1p or Tup1p could be considerably enhanced. Immunologic detection of C-terminally tagged Tsa1p and Tup1p upon UV irradiation in a strain background containing suppressor tRNA and optimized AzF-RS revealed not only the mutant monomeric forms of these proteins but also higher-molecularweight complexes, strictly depending on the specific position of incorporated AzF and UV excitation. By Western blotting and tandem mass spectrometry, we could identify these higher-molecular-weight complexes as homodimers consisting of one mutant monomer and a differently tagged, wild-type version of Tsa1p or Tup1p, respectively, demonstrating that expanding the genetic code of C. albicans with the unnatural photo-cross-linker amino acid AzF and applying it for in vivo binary protein interaction analyses is feasible.

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A family of secreted pathogenesis‐related proteins in Candida albicans

Cited by 30 publications

References 68 publications

Candidalysin is a fungal peptide toxin critical for mucosal infection

Candidalysin is a fungal peptide toxin critical for mucosal infection

Comparative Evolution of Morphological Regulatory Functions in Candida Species

An Expanded Genetic Code in Candida albicans To Study Protein-Protein Interactions In Vivo

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