The TRK1 Potassium Transporter Is the Critical Effector for Killing of Candida albicans by the Cationic Protein, Histatin 5

Baev, Didi; Rivetta, Alberto; Vylkova, Slavena; Sun, Jianing N.; Zeng, Ge Fei; Slayman, Clifford L.; Edgerton, Mira

doi:10.1074/jbc.m411031200

Cited by 72 publications

(77 citation statements)

References 58 publications

(39 reference statements)

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“…To assess the potential for SSD1 specificity in antimicrobial peptide resistance, MICs of nonpeptide agents were determined using standard broth macrodilution methods as previously described (2,42). For these studies, a panel of agents was selected based on the following distinct targets of fungal cell disruption: hydrogen peroxide (H 2 O 2 ; range, 100 to 0.2 mM; oxidative injury); sodium dodecyl sulfate (SDS; range, 0.1 to 0.0001% [wt/vol]; lipid membrane disruptant); and amphotericin B (AMB; range, 10 to 0.02 g/ml; polyene antagonist of ergesterol).…”

Section: Methodsmentioning

confidence: 99%

SSD1 Is Integral to Host Defense Peptide Resistance in Candida albicans

et al. 2008

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Candida albicans is usually a harmless human commensal. Because inflammatory responses are not normally induced by colonization, antimicrobial peptides are likely integral to first-line host defense against invasive candidiasis. Thus, C. albicans must have mechanisms to tolerate or circumvent molecular effectors of innate immunity and thereby colonize human tissues. Prior studies demonstrated that an antimicrobial peptideresistant strain of C. albicans, 36082 R , is hypervirulent in animal models versus its susceptible counterpart (36082 S ). The current study aimed to identify a genetic basis for antimicrobial peptide resistance in C. albicans. Screening of a C. albicans genomic library identified SSD1 as capable of conferring peptide resistance to a susceptible surrogate, Saccharomyces cerevisiae. Sequencing confirmed that the predicted translation products of 36082 S and 36082 R SSD1 genes were identical. However, Northern analyses corroborated that SSD1 is expressed at higher levels in 36082 R than in 36082 S . In isogenic backgrounds, ssd1⌬/ssd1⌬ null mutants were significantly more susceptible to antimicrobial peptides than parental strains but had equivalent susceptibilities to nonpeptide stressors. Moreover, SSD1 complementation of ssd1⌬/ssd1⌬ mutants restored parental antimicrobial peptide resistance phenotypes, and overexpression of SSD1 conferred enhanced peptide resistance. Consistent with these in vitro findings, ssd1 null mutants were significantly less virulent in a murine model of disseminated candidiasis than were their parental or complemented strains. Collectively, these results indicate that SSD1 is integral to C. albicans resistance to host defense peptides, a phenotype that appears to enhance the virulence of this organism in vivo.

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Section: Methodsmentioning

confidence: 99%

SSD1 Is Integral to Host Defense Peptide Resistance in Candida albicans

et al. 2008

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“…Pharmacological inhibitors of anion transporters significantly prevented volume reduction and killing, suggesting that volume loss is a result of ion efflux (22). Subsequently, Trk1 was identified as an ion transporter responsible for potassium loss, since cells lacking the protein were resistant to Hst 5 (43). Another observation, in line with such volume dysregulation, is that vacuolar expansion was also observed along with cytosolic translocation, but in either case, PI uptake (indicative of cell lysis) always followed but never preceded vacuolar expansion (29).…”

Section: Cell Death By Ionic Imbalance and Volume Dysregulationmentioning

confidence: 99%

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

2014

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Histatins are salivary cationic peptides that provide the first line of defense against oral candidiasis caused by Candida albicans. This minireview presents a critical evaluation of our knowledge of the candidacidal mechanism of histatin 5 (Hst 5). Hst 5 is the most potent among all histatin family members with regard to its antifungal activity. The mode of action of Hst 5 has been a subject of intense debate. Unlike other classical host innate immune proteins, pore formation or membrane lysis by Hst 5 has largely been disproven, and it is now known that all targets of Hst 5 are intracellular. Hst 5 binds C. albicans cell wall proteins (Ssa1/2) and glycans and is taken up by the cells through fungal polyamine transporters in an energy-dependent manner. Once inside the fungal cells, Hst 5 may affect mitochondrial functions and cause oxidative stress; however, the ultimate cause of cell death is by volume dysregulation and ion imbalance triggered by osmotic stress. Besides these diverse targets, a novel mechanism based on the metal binding abilities of Hst 5 is discussed. Finally, translational approaches for Hst 5, based on peptide design and synergy with other known drugs, are considered a step forward for bench-to-bed application of Hst 5.

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“…TRK1 encodes the potassium transporter. Attempts to delete the second allele were unsuccessful, suggesting that TRK1 is an essential gene (14). However, the deletion of one allele resulted in reduced histatin 5 killing, histatin 5 induced ATP release, and the influx of K ϩ (measured as 86 R ϩ ) was reduced five-to sevenfold.…”

Section: Mp65pmentioning

confidence: 99%

Candida albicansCell Wall Proteins

Chaffin

2008

Microbiol Mol Biol Rev

435

404

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SUMMARY The Candida albicans cell wall maintains the structural integrity of the organism in addtion to providing a physical contact interface with the environment. The major components of the cell wall are fibrillar polysaccharides and proteins. The proteins of the cell wall are the focus of this review. Three classes of proteins are present in the candidal cell wall. One group of proteins attach to the cell wall via a glycophosphatidylinositol remnant or by an alkali-labile linkage. A second group of proteins with N-terminal signal sequences but no covalent attachment sequences are secreted by the classical secretory pathway. These proteins may end up in the cell wall or in the extracellular space. The third group of proteins lack a secretory signal, and the pathway(s) by which they become associated with the surface is unknown. Potential constituents of the first two classes have been predicted from analysis of genome sequences. Experimental analyses have identified members of all three classes. Some members of each class selected for consideration of confirmed or proposed function, phenotypic analysis of a mutant, and regulation by growth conditions and transcription factors are discussed in more detail.

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The TRK1 Potassium Transporter Is the Critical Effector for Killing of Candida albicans by the Cationic Protein, Histatin 5

Cited by 72 publications

References 58 publications

SSD1 Is Integral to Host Defense Peptide Resistance in Candida albicans

SSD1 Is Integral to Host Defense Peptide Resistance in Candida albicans

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

Candida albicansCell Wall Proteins

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