Calcium-calcineurin signaling pathway in Candida albicans: A potential drug target

Li, Wanqian; Shrivastava, Manjari; Lu, Hui; Jiang, Yuanying

doi:10.1016/j.micres.2021.126786

Cited by 16 publications

(4 citation statements)

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“…Calcineurin plays an essential role in the FLC tolerance of C. albicans ( 8 ), and Hsp90 contributes to FLC tolerance by stabilizing calcineurin ( 9 , 17 , 37 ). Therefore, inhibitors of calcineurin (cyclosporine) and Hsp90 (geldanamycin) can make FLC fungicidal ( 9 , 15 ) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…These adjuvants work by inhibiting proteins that play an essential role in FLC tolerance; inhibitors of calcineurin (cyclosporine and FK506), Hsp90 (geldanamycin), TOR (rapamycin), and a guanine nucleotide exchange factor (brefeldin A) can make FLC fungicidal ( 6 , 10 , 15 , 16 ). However, the clinical applications of these drug combinations are limited because of their high levels of toxicity ( 17 ). Therefore, adjuvants are needed that inactivate new synergistic targets to make FLC fungicidal.…”

Section: Introductionmentioning

confidence: 99%

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A Small Molecule Inhibitor of Erg251 Makes Fluconazole Fungicidal by Inhibiting the Synthesis of the 14α-Methylsterols

Whiteway

et al. 2023

mBio

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Fluconazole (FLC) tolerance increases the frequency of acquired FLC resistance, and a high FLC tolerance level is associated with persistent candidemia. Multiple functional proteins, such as calcineurin, heat shock protein 90 (Hsp90), and ADP ribosylation factor, are essential for the survival of C. albicans exposed to FLC, but how these factors increase the fungicidal activity of FLC remains to be determined.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Small Molecule Inhibitor of Erg251 Makes Fluconazole Fungicidal by Inhibiting the Synthesis of the 14α-Methylsterols

Whiteway

et al. 2023

mBio

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“…The observation that calcineurin induces unmasking during both hyperactive STE11 ΔN467 expression and in response to caspofungin ( Fig 1 ) raised the possibility that the calcineurin pathway may induce unmasking upon direct stimulation. The calmodulin/calcineurin pathway mediates signaling in response to high levels of exogenous calcium [ 50 , 51 ]. We hypothesized that activation of the calcineurin pathway via calcium addition would also increase ß(1,3)-glucan exposure.…”

Section: Resultsmentioning

confidence: 99%

Cek1 regulates ß(1,3)-glucan exposure through calcineurin effectors in Candida albicans

et al. 2022

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In order to successfully induce disease, the fungal pathogen Candida albicans regulates exposure of antigens like the cell wall polysaccharide ß(1,3)-glucan to the host immune system. C. albicans covers (masks) ß(1,3)-glucan with a layer of mannosylated glycoproteins, which aids in immune system evasion by acting as a barrier to recognition by host pattern recognition receptors. Consequently, enhanced ß(1,3)-glucan exposure (unmasking) makes fungal cells more visible to host immune cells and facilitates more robust fungal clearance. However, an understanding of how C. albicans regulates its exposure levels of ß(1,3)-glucan is needed to leverage this phenotype. Signal transduction pathways and their corresponding effector genes mediating these changes are only beginning to be defined. Here, we report that the phosphatase calcineurin mediates unmasking of ß(1,3)-glucan in response to inputs from the Cek1 MAPK pathway and in response to caspofungin exposure. In contrast, calcineurin reduces ß-glucan exposure in response to high levels of extracellular calcium. Thus, depending on the input, calcineurin acts as a switchboard to regulate ß(1,3)-glucan exposure levels. By leveraging these differential ß(1,3)-glucan exposure phenotypes, we identified two novel effector genes in the calcineurin regulon, FGR41 and C1_11990W_A, that encode putative cell wall proteins and mediate masking/unmasking. Loss of either effector caused unmasking and attenuated virulence during systemic infection in mice. Furthermore, immunosuppression restored the colonization decrease seen in mice infected with the fgr41Δ/Δ mutant to wild-type levels, demonstrating a reliance on the host immune system for virulence attenuation. Thus, calcineurin and its downstream regulon are general regulators of unmasking.

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“…Being Ca 2+ an essential signaling ion, proteins involved in its homeostasis are increasingly studied as potential targets of antifungal drugs ( Kwun et al, 2021 ; Li et al, 2021 ; Wang et al, 2021 ). A model of Ca 2+ signaling could be used to predict the outcomes of the inhibition of a particular protein on the calcium physiology of fungal cells, thus helping to identify the best drug targets.…”

Section: Discussionmentioning

confidence: 99%

Modeling Calcium Signaling in S. cerevisiae Highlights the Role and Regulation of the Calmodulin-Calcineurin Pathway in Response to Hypotonic Shock

Spolaor

Rovetta

Nobile

et al. 2022

Front. Mol. Biosci.

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Calcium homeostasis and signaling processes in Saccharomyces cerevisiae, as well as in any eukaryotic organism, depend on various transporters and channels located on both the plasma and intracellular membranes. The activity of these proteins is regulated by a number of feedback mechanisms that act through the calmodulin-calcineurin pathway. When exposed to hypotonic shock (HTS), yeast cells respond with an increased cytosolic calcium transient, which seems to be conditioned by the opening of stretch-activated channels. To better understand the role of each channel and transporter involved in the generation and recovery of the calcium transient—and of their feedback regulations—we defined and analyzed a mathematical model of the calcium signaling response to HTS in yeast cells. The model was validated by comparing the simulation outcomes with calcium concentration variations before and during the HTS response, which were observed experimentally in both wild-type and mutant strains. Our results show that calcium normally enters the cell through the High Affinity Calcium influx System and mechanosensitive channels. The increase of the plasma membrane tension, caused by HTS, boosts the opening probability of mechanosensitive channels. This event causes a sudden calcium pulse that is rapidly dissipated by the activity of the vacuolar transporter Pmc1. According to model simulations, the role of another vacuolar transporter, Vcx1, is instead marginal, unless calcineurin is inhibited or removed. Our results also suggest that the mechanosensitive channels are subject to a calcium-dependent feedback inhibition, possibly involving calmodulin. Noteworthy, the model predictions are in accordance with literature results concerning some aspects of calcium homeostasis and signaling that were not specifically addressed within the model itself, suggesting that it actually depicts all the main cellular components and interactions that constitute the HTS calcium pathway, and thus can correctly reproduce the shaping of the calcium signature by calmodulin- and calcineurin-dependent complex regulations. The model predictions also allowed to provide an interpretation of different regulatory schemes involved in calcium handling in both wild-type and mutants yeast strains. The model could be easily extended to represent different calcium signals in other eukaryotic cells.

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Calcium-calcineurin signaling pathway in Candida albicans: A potential drug target

Cited by 16 publications

References 91 publications

A Small Molecule Inhibitor of Erg251 Makes Fluconazole Fungicidal by Inhibiting the Synthesis of the 14α-Methylsterols

A Small Molecule Inhibitor of Erg251 Makes Fluconazole Fungicidal by Inhibiting the Synthesis of the 14α-Methylsterols

Cek1 regulates ß(1,3)-glucan exposure through calcineurin effectors in Candida albicans

Modeling Calcium Signaling in S. cerevisiae Highlights the Role and Regulation of the Calmodulin-Calcineurin Pathway in Response to Hypotonic Shock

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