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Calcineurin fungi

Patricia Hernández-Ortiz, Eduardo A Espeso
The response of Aspergilli to elevated concentrations of extracellular calcium and manganese, or environmental alkalinization is mediated by CrzA, a calcineurin-responsive transcription factor (TF). CrzA is the effector of a signaling pathway which includes the apical protein's calmodulin and calcineurin, and the protein kinases GskA and CkiA. Preferentially located in the cytoplasm, CrzA is the only element of the pathway modifying its localization under those stress conditions, being imported into nuclei...
January 2017: Cellular Signalling
Xiaokui Gu, Wei Xue, Yajing Yin, Hongwei Liu, Shaojie Li, Xianyun Sun
Heat Shock Protein 90 (Hsp90) is essential for tumor progression in humans and drug resistance in fungi. However, the roles of its many co-chaperones in antifungal resistance are unknown. In this study, by susceptibility test of Neurospora crassa mutants lacking each of 18 Hsp90/Calcineurin system member genes (including 8 Hsp90 co-chaperone genes) to antifungal drugs and other stresses, we demonstrate that the Hsp90 co-chaperones Sti1 (Hop1 in yeast), Aha1, and P23 (Sba1 in yeast) were required for the basal resistance to antifungal azoles and heat stress...
2016: Frontiers in Microbiology
Yutaka Tanaka, Masato Sasaki, Fumie Ito, Toshio Aoyama, Michiyo Sato-Okamoto, Azusa Takahashi-Nakaguchi, Hiroji Chibana, Nobuyuki Shibata
The maintenance of cell wall integrity in fungi is required for normal cell growth, division, hyphae formation, and antifungal tolerance. We observed that endoplasmic reticulum stress regulated cell wall integrity in Candida glabrata, which possesses uniquely evolved mechanisms for unfolded protein response mechanisms. Tetracycline-mediated suppression of KRE5, which encodes a predicted UDP-glucose:glycoprotein glucosyltransferase localized in the endoplasmic reticulum, significantly increased cell wall chitin content and decreased cell wall β-1,6-glucan content...
2016: PloS One
Josué Delgado, Rebecca A Owens, Sean Doyle, Miguel A Asensio, Félix Núñez
Moulds growing on the surface of dry-ripened foods contribute to their sensory qualities, but some of them are able to produce mycotoxins that pose a hazard to consumers. Small cysteine-rich antifungal proteins (AFPs) from moulds are highly stable to pH and proteolysis and exhibit a broad inhibition spectrum against filamentous fungi, providing new chances to control hazardous moulds in fermented foods. The analytical tools for characterizing the cellular targets and affected pathways are reviewed. Strategies currently employed to study these mechanisms of action include 'omics' approaches that have come to the forefront in recent years, developing in tandem with genome sequencing of relevant organisms...
August 2016: Applied Microbiology and Biotechnology
Won Jeong Lee, Jae Sun Moon, Young Tae Kim, Tran The Bach, Do Van Hai, Sung Uk Kim
In order to discover plant-derived signaling pathway inhibitors with antifungal properties, a two-component screening system utilizing the calcineurin and Hog1 mitogen-activated protein kinase pathways responsible for the virulence networks of Cryptococcus neoformans was employed, owing to the counter-regulatory actions of these pathways. Of the 1,000 plant extracts tested, two bioactive compounds from Miliusa sinensis were found to act specifically on the calcineurin pathway of C. neoformans. These compounds, identified as pashanone and 5-hydroxy-6,7-dimethoxyflavanone, exhibited potent antifungal activities against various human pathogenic fungi with minimum inhibitory concentration values ranging from 4...
October 28, 2016: Journal of Microbiology and Biotechnology
Hélène Martin-Yken, Jean Marie François, Didier Zerbib
The most highly connected proteins in protein-protein interactions networks are called hubs; they generally connect signalling pathways. In Saccharomyces cerevisiae, Knr4 constitutes a connecting node between the two main signal transmission pathways involved in cell wall maintenance upon stress: the cell wall integrity and the calcium-calcineurin pathway. Knr4 is required to enable the cells to resist many cell wall-affecting stresses, and KNR4 gene deletion is synthetic lethal with the simultaneous deletion of numerous other genes involved in morphogenesis and cell wall biogenesis...
September 2016: Cellular Microbiology
Sébastien Imbert, Priscillia Bresler, Alexandre Boissonnas, Lauraine Gauthier, Laëtitia Souchet, Madalina Uzunov, Véronique Leblond, Dominique Mazier, Stéphanie Nguyen, Arnaud Fekkar
BACKGROUND: Neutrophils are key effectors against the widely distributed mold Aspergillus fumigatus, which is a major threat for immunocompromised patients, including allogeneic hematopoietic stem cell transplant (HSCT) recipients. Yet little is known about neutrophil activity over time after cell transplantation, especially regarding A fumigatus. OBJECTIVE: We aimed at assessing the activity of neutrophils on A fumigatus in allogeneic HSCT recipients at different posttransplantation time points...
September 2016: Journal of Allergy and Clinical Immunology
Nam K Tonthat, Praveen Rao Juvvadi, Hengshan Zhang, Soo Chan Lee, Ron Venters, Leonard Spicer, William J Steinbach, Joseph Heitman, Maria A Schumacher
UNLABELLED: Invasive fungal infections remain difficult to treat and require novel targeting strategies. The 12-kDa FK506-binding protein (FKBP12) is a ubiquitously expressed peptidyl-prolyl isomerase with considerable homology between fungal pathogens and is thus a prime candidate for future targeting efforts to generate a panfungal strategy. Despite decades of research on FKBPs, their substrates and mechanisms of action remain unclear. Here we describe structural, biochemical, and in vivo analyses of FKBP12s from the pathogenic fungi Candida albicans, Candida glabrata, and Aspergillus fumigatus Strikingly, multiple apo A...
April 26, 2016: MBio
Ling Chen, Gen Zou, Jingzhi Wang, Jin Wang, Rui Liu, Yanping Jiang, Guoping Zhao, Zhihua Zhou
Calcium signaling plays pivotal roles in the hyphal growth, conidiation, and osmosis sensitivity of fungi through the Ca(2+) /calmodulin-calcineurin-dependent pathway. This study found that an appropriate extracellular Ca(2+) concentration markedly stimulated the hyphal growth, cellulase production, and total protein secretion of the cellulase hyper-producing strain, Trichoderma reesei Rut-C30. Transcription analysis revealed upregulation of not only encoding genes of cellulases and the transcriptional activator XYR1 but also several genes encoding endoplasmic reticulum-chaperones after Ca(2+) addition...
May 2016: Molecular Microbiology
Sha Wang, Xiao Liu, Hui Qian, Shizhu Zhang, Ling Lu
The eukaryotic calcium/calmodulin-dependent protein phosphatase calcineurin is crucial for the environmental adaption of fungi. However, the mechanism of coordinate regulation of the response to salt stress by calcineurin and the high-affinity calcium channel CchA in fungi is not well understood. Here we show that the deletion of cchA suppresses the hyphal growth defects caused by the loss of calcineurin under salt stress in Aspergillus nidulans Additionally, the hypersensitivity of the ΔcnaA strain to extracellular calcium and cell-wall-damaging agents can be suppressed by cchA deletion...
June 1, 2016: Applied and Environmental Microbiology
Feng He, Xiong Zhang, Joseph Juma Mafurah, Meixiang Zhang, Guoliang Qian, Rongbo Wang, Asma Safdar, Xiaolei Yang, Fengquan Liu, Daolong Dou
Valsa pyri is a fatal pathogenic fungus that causes pear and apple canker disease. To date, its cellular development and pathogenicity have been poorly understood. In this study, a V. pyri Ca(2+)/calcineurin-dependent transcription factor CRZ1 (VpCRZ1) is identified and functionally characterized. The △VpCRZ1 mutant exhibits impaired pathogenicity and is no longer able to form fruiting body. Interestingly, this mutant also exhibits enhanced pigment deposition and increased resistance to cell wall perturbing agents including SDS, Congo red and calcofluor white (CFW)...
June 2016: Microbial Pathogenesis
Eduardo A Espeso
Calcium is an essential cation for a cell. This cation participates in the regulation of numerous processes in either prokaryotes or eukaryotes, from bacteria to humans. Saccharomyces cerevisiae has served as a model organism to understand calcium homeostasis and calcium-dependent signaling in fungi. In this chapter it will be reviewed known and predicted transport mechanisms that mediate calcium homeostasis in the yeast. How and when calcium enters the cell, how and where it is stored, when is reutilized, and finally secreted to the environment to close the cycle...
2016: Advances in Experimental Medicine and Biology
Chi Zhang, Xiuhua Meng, Xiaolei Wei, Ling Lu
Filamentous fungi have a dominant nonhomologous-end joining (NHEJ) DNA repair pathway, which results in the majority of transformed progenies having random heterologous insertion mutagenesis. Thus, lack of a versatile genome-editing tool prevents us from carrying out precise genome editing to explore the mechanism of pathogenesis. Moreover, clinical isolates that have a wild-type ku80 background without any selection nutrition marker especially suffer from low homologous integration efficiency. In this study, we have established a highly efficient CRISPR mutagenesis system to carry out precise and efficient in-frame integration with or without marker insertion with approximately 95-100% accuracy via very short (approximately 35-bp) homology arms in a process referred to as microhomology-mediated end joining (MMEJ)...
January 2016: Fungal Genetics and Biology: FG & B
Xibo Zhang, Yue Fang, Wurentuya Jaiseng, Lingling Hu, Yabin Lu, Yan Ma, Tomoyuki Furuyashiki
Tamoxifen, a selective estrogen receptor modulator used for managing breast cancer, is known to have antifungal activity. However, its molecular mechanism remains unknown. Using the fission yeast Schizosaccharomyces pombe as a model organism, we have explored the mechanism involved in antifungal action of tamoxifen. Since tamoxifen was shown to inhibit the binding of calmodulin to calcineurin in fungi, we first examined involvement of these molecules and found that overexpression of a catalytic subunit of calcineurin and its constitutively active mutant as well as calmodulin increases tamoxifen sensitivity...
2015: Kobe Journal of Medical Sciences
Katie Falloon, Praveen R Juvvadi, Amber D Richards, José M Vargas-Muñiz, Hilary Renshaw, William J Steinbach
Invasive aspergillosis, largely caused by Aspergillus fumigatus, is responsible for a growing number of deaths among immunosuppressed patients. Immunosuppressants such as FK506 (tacrolimus) that target calcineurin have shown promise for antifungal drug development. FK506-binding proteins (FKBPs) form a complex with calcineurin in the presence of FK506 (FKBP12-FK506) and inhibit calcineurin activity. Research on FKBPs in fungi is limited, and none of the FKBPs have been previously characterized in A. fumigatus...
2015: PloS One
Dianguang Xiong, Yonglin Wang, Chen Tang, Yulin Fang, Jingyi Zou, Chengming Tian
Calcium signaling plays crucial roles in ion stress tolerance, sporulation and pathogenicity in fungi. Although the signaling pathway mediated by calcineurin and the calcineurin-responsive zinc finger transcription factor Crz1 is well characterized in other fungi, this pathway is not well characterized in the phytopathogenic fungus, Verticillium dahliae. To better understand the role of this calcineurin-dependent transcription factor in V. dahliae, an ortholog of CRZ1, VdCrz1, was identified and characterized functionally...
September 2015: Fungal Genetics and Biology: FG & B
Kangji Wang, Zhenying Zhang, Xi Chen, Xianyun Sun, Cheng Jin, Hongwei Liu, Shaojie Li
Azoles are commonly used as antifungal drugs or pesticides to control fungal infections in medicine and agriculture. Fungi adapt to azole stress by rapidly activating the transcription of a number of genes, and transcriptional increases in some azole-responsive genes can elevate azole resistance. The regulatory mechanisms that control transcriptional responses to azole stress in filamentous fungi are not well understood. This study identified a bZIP transcription factor, ADS-4 (antifungal drug sensitive-4), as a new regulator of adaptive responses and resistance to antifungal azoles...
September 2015: Antimicrobial Agents and Chemotherapy
Soo Chan Lee, Alicia Li, Silvia Calo, Makoto Inoue, Nam K Tonthat, Judith M Bain, Johanna Louw, Mari L Shinohara, Lars P Erwig, Maria A Schumacher, Dennis C Ko, Joseph Heitman
Calcineurin plays essential roles in virulence and growth of pathogenic fungi and is a target of the natural products FK506 and Cyclosporine A. In the pathogenic mucoralean fungus Mucor circinelloides, calcineurin mutation or inhibition confers a yeast-locked phenotype indicating that calcineurin governs the dimorphic transition. Genetic analysis in this study reveals that two calcineurin A catalytic subunits (out of three) are functionally diverged. Homology modeling illustrates modes of resistance resulting from amino substitutions in the interface between each calcineurin subunit and the inhibitory drugs...
September 2015: Molecular Microbiology
Asif Khan, Elie El-Charabaty, Suzanne El-Sayegh
Organ transplantation has always been considered to be the standard therapeutic interventions in patients with end-stage organ failure. In 2008, more than 29,000 organ transplants were performed in US. Survival rates among transplant recipients have greatly improved due to better understanding of transplant biology and more effective immunosuppressive agents. After transplant, the extent of the immune response is influenced by the amount of interleukin 2 (IL-2) being produced by the T-helper cells. Transplant immunosuppressive therapy primarily targets T cell-mediated graft rejection...
June 2015: Journal of Clinical Medicine Research
Praveen R Juvvadi, Yan Ma, Amber D Richards, Erik J Soderblom, M Arthur Moseley, Frédéric Lamoth, William J Steinbach
Calcineurin is a key protein phosphatase required for hyphal growth and virulence in Aspergillus fumigatus, making it an attractive antifungal target. However, currently available calcineurin inhibitors, FK506 and cyclosporine A, are immunosuppressive, limiting usage in the treatment of patients with invasive aspergillosis. Therefore, the identification of endogenous inhibitors of calcineurin belonging to the calcipressin family is an important parallel strategy. We previously identified the gene cbpA as the A...
2015: Frontiers in Microbiology
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