Histatin 5 Initiates Osmotic Stress Response in
            <i>Candida albicans</i>
            via Activation of the Hog1 Mitogen-Activated Protein Kinase Pathway

Vylkova, Slavena; Jang, Woong Sik; Li, Wansheng; Nayyar, Namrata; Edgerton, Mira

doi:10.1128/ec.00039-07

Cited by 81 publications

(62 citation statements)

References 44 publications

(51 reference statements)

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“…Hst 5 treatment of C. albicans caused Hog1 phosphorylation, and hog1⌬/⌬ mutants were found to be more susceptible to Hst 5 (54). Hog1-induced glycerol production was enhanced in cells exposed to Hst 5 (54). All this corroborated with the proposed induction of osmotic stress as an important mechanistic mediator in Hst 5 candidacidal activity.…”

Section: Involvement Of Mapk Signalingsupporting

confidence: 83%

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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Section: Involvement Of Mapk Signalingsupporting

confidence: 83%

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

2014

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“…Treatment with histatin 5, another antimicrobial peptide, has been recently shown to cause activation of Hog1, as well as the core and osmotic-stress transcriptional responses (20). Taken together, this and our results suggest that the Hog1 kinase plays a key role in the response to antimicrobial peptides.…”

supporting

confidence: 71%

“…albicans has been shown to initiate an osmotic-stress response to histatin 5, a salivary antimicrobial peptide, via activation of the high-osmolarity glycerol (HOG) mitogen-activated protein kinase (MAPK) pathway (20). Histatins and ␤-defensins have different structural properties and roles in human immunity (2).…”

mentioning

confidence: 99%

Interaction between the Candida albicans High-Osmolarity Glycerol (HOG) Pathway and the Response to Human β-Defensins 2 and 3

et al. 2011

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“…albicans Hog1 SAPK is activated by many environmental cues, including osmotic and oxidative stimuli, heavy metal, glucose, and cationic peptides (45,(49)(50)(51). Two of them, oxidativestress levels and glucose concentrations, have been reported to be involved in opaque-cell formation and its stability (32,34,52).…”

Section: Discussionmentioning

confidence: 99%

A Novel Function for Hog1 Stress-Activated Protein Kinase in Controlling White-Opaque Switching and Mating in Candida albicans

et al. 2014

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Candida albicans is a commensal in heathy people but has the potential to become an opportunistic pathogen and is responsible for half of all clinical infections in immunocompromised patients. Central to understanding C. albicans behavior is the whiteopaque phenotypic switch, in which cells can undergo an epigenetic transition between the white state and the opaque state. The phenotypic switch regulates multiple properties, including biofilm formation, virulence, mating, and fungus-host interactions. Switching between the white and opaque states is associated with many external stimuli, such as oxidative stress, pH, and N-acetylglucosamine, and is directly regulated by the Wor1 transcriptional circuit. The Hog1 stress-activated protein kinase (SAPK) pathway is recognized as the main pathway for adapting to environmental stress in C. albicans. In this work, we first show that loss of the HOG1 gene in a/a and ␣/␣ cells, but not a/␣ cells, results in 100% white-to-opaque switching when cells are grown on synthetic medium, indicating that switching is repressed by the a1/␣2 heterodimer that represses WOR1 gene expression. Indeed, switching in the hog1⌬ strain was dependent on the presence of WOR1, as a hog1⌬ wor1⌬ strain did not show switching to the opaque state. Deletion of PBS2 and SSK2 also resulted in C. albicans cells switching from white to opaque with 100% efficiency, indicating that the entire Hog1 SAPK pathway is involved in regulating this unique phenotypic transition. Interestingly, all Hog1 pathway mutants also caused defects in shmoo formation and mating efficiencies. Overall, this work reveals a novel role for the Hog1 SAPK pathway in regulating white-opaque switching and sexual behavior in C. albicans.

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Histatin 5 Initiates Osmotic Stress Response in Candida albicans via Activation of the Hog1 Mitogen-Activated Protein Kinase Pathway

Cited by 81 publications

References 44 publications

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

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

Interaction between the Candida albicans High-Osmolarity Glycerol (HOG) Pathway and the Response to Human β-Defensins 2 and 3

A Novel Function for Hog1 Stress-Activated Protein Kinase in Controlling White-Opaque Switching and Mating in Candida albicans

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