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Calcineurin fungi

Omar Loss, Margherita Bertuzzi, Yu Yan, Natalie Fedorova, Bethany L McCann, Darius Armstrong-James, Eduardo A Espeso, Nick D Read, William C Nierman, Elaine M Bignell
Functional coupling of calcium- and alkaline responsive signalling occurs in multiple fungi to afford efficient cation homeostasis. Host microenvironments exert alkaline stress and potentially toxic concentrations of Ca(2+) , such that highly conserved regulators of both calcium- (Crz) and pH- (PacC/Rim) responsive signalling are crucial for fungal pathogenicity. Drugs targeting calcineurin are potent antifungal agents but also perturb human immunity thereby negating their use as anti-infectives, abrogation of alkaline signalling has therefore been postulated as an adjunctive antifungal strategy...
September 18, 2017: Molecular Microbiology
Sha Wang, Hongchang Zhou, Jun Wu, Jiangyu Han, Shasha Li, Shengwen Shao
Adaptation to changes in the environment is crucial for the viability of all organisms. Although the importance of calcineurin in the stress response has been highlighted in filamentous fungi, little is known about the involvement of ion-responsive genes and pathways in conferring salt tolerance without calcium signaling. In this study, high-throughput RNA-seq was used to investigate salt stress-induced genes in the parent, ΔcnaB, and ΔcnaBΔcchA strains of Aspergillus nidulans, which differ greatly in salt adaption...
2017: BioMed Research International
Mohammad Khairy El-Badrawy, Raed El-Metwaly Ali, Amr Yassen, Mohammad Ahmad AbouElela, Rehab Ahmad Elmorsey
OBJECTIVES: Pneumonia has a negative effect on the outcome of liver transplant. Our aim was to analyze early-onset pneumonia that developed within the first month after transplant. MATERIALS AND METHODS: This prospective single-center study included 56 adult living-donor liver transplant recipients; those who developed early-onset pneumonia based on clinical and radiologic criteria were investigated as to causative pathogens and then followed up and compared with other recipients without pneumonia to illustrate risk factors, outcomes, and related mortality of posttransplant pneumonia...
October 2017: Experimental and Clinical Transplantation
Sarah Sze Wah Wong, Orhan Rasid, Paris Laskaris, Arnaud Fekkar, Jean-Marc Cavaillon, William J Steinbach, Oumaima Ibrahim-Granet
Cyclosporin A (CsA) is widely used as an immunosuppressive agent for organ transplant recipients. CsA inhibits calcineurin, which is highly conserved in mammals and fungi, and thus affects both types of organism. In mammals, the immunosuppressive effect of CsA is via hampering T cell activation. In fungi, the growth inhibitory effect of CsA is via interference with hyphal growth. The aim of this study was to determine whether CsA renders mice susceptible to invasive pulmonary aspergillosis (IPA) and whether it can protect immunosuppressed mice from infection...
June 8, 2017: Virulence
Josué Delgado, Rebecca A Owens, Sean Doyle, Félix Núñez, Miguel A Asensio
The ability of Aspergillus flavus to produce aflatoxins in dairy products presents a potential hazard. The antifungal protein PgAFP from Penicillium chrysogenum inhibits various foodborne toxigenic fungi, including Aspergillus flavus. However, PgAFP did not inhibit A. flavus growth in cheese, which was related to the associated cation content. CaCl2 increased A. flavus permeability and prevented PgAFP-mediated inhibition in potato dextrose broth (PDB). PgAFP did not elicit any additional increase in permeability of CaCl2-incubated A...
September 2017: Food Microbiology
Shenghua Zhang, Hailin Zheng, Qiuyi Chen, Yuan Chen, Sha Wang, Ling Lu, Shizhu Zhang
The Ca(2+)-mediated signaling pathway is crucial for environmental adaptation in fungi. Here we show that calnexin, a molecular chaperone located in the endoplasmic reticulum (ER), plays an important role in regulating the cytosolic free calcium concentration ([Ca(2+)]c) in Aspergillus nidulans Inactivation of calnexin (ClxA) in A. nidulans caused severe defects in hyphal growth and conidiation under ER stress caused by the ER stress-inducing agent dithiothreitol (DTT) or high temperature. Importantly, defects in the ΔclxA mutant were restored by the addition of extracellular calcium...
August 1, 2017: Applied and Environmental Microbiology
Alexis Garcia, Gloria Adedoyin, Joseph Heitman, Soo Chan Lee
Mucor circinelloides is a human pathogen, biofuel producer, and model system that belongs to a basal fungal lineage; however, the genetics of this fungus are limited. In contrast to ascomycetes and basidiomycetes, basal fungal lineages have been understudied. This may be caused by a lack of attention given to these fungi, as well as limited tools for genetic analysis. Nonetheless, the importance of these fungi as pathogens and model systems has increased. M. circinelloides is one of a few genetically tractable organisms in the basal fungi, but it is far from a robust genetic system when compared to model fungi in the subkingdom Dikarya...
July 5, 2017: G3: Genes—Genomes—Genetics
Xing Chen, Yuanze Liu, Nemat O Keyhani, Yuxian Xia, Yueqing Cao
In fungi, the Ca(2+)/calcineurin signaling pathway is critical in mediating growth, morphology, stress responses, and pathogenicity. Crz1 is a calcineurin-responsive zinc finger transcription factor. Here, MaCrz1 was identified and functionally characterized in the entomopathogenic fungus Metarhizium acridum by characterization of a targeted gene knockout strain. Conidia of the ΔMacrz1 mutant were aberrant in cell surface features and lacked the characteristic hydrophobic rodlet layer, and the mutant displayed increased sensitivity to oxidative stress, cell wall perturbing agents, heat stress, and ultraviolet irradiation as compared to the wild-type and complemented strains...
June 2017: Applied Microbiology and Biotechnology
Mitchell Nambu, Jonathan A Covel, Mili Kapoor, Xiaoming Li, Molly K Moloney, Mehdi M Numa, Quinlyn A Soltow, Michael Trzoss, Peter Webb, Robert R Webb, Mitchell Mutz
A novel antifungal strategy targeting the inhibition of calcineurin is described. To develop a calcineurin based inhibitor of pathogenic fungi, analogs of FK506 were synthesized that were able to permeate mammalian but not fungal cells. Antagonists in combination with FK506 were not immunosuppressive and retained antifungal activity in A. fumigatus. To reduce the dosage burden of the antagonist, murine oral PK was improved an order of magnitude relative to previous FK506 antagonists.
April 3, 2017: Bioorganic & Medicinal Chemistry Letters
Ciamak Ghazaei
The virulence of fungi is dependent on multiple factors, including the immune status of patients and biological features of fungi. In particular, the virulence of Aspergillus fumigatus is due to the complex interaction among various molecules involved in thermotolerance (such as ribosomal biogenesis proteins, α-mannosyltransferase and heat shock proteins), pigment production (DHN-melanin), immune evasion (like melanin and hydrophobin) and nutrient uptake (such as siderophores and zinc transporters). Other molecules also play important roles in the virulence of A...
March 2017: Malaysian Journal of Medical Sciences: MJMS
Eve W L Chow, Shelly A Clancey, R Blake Billmyre, Anna Floyd Averette, Joshua A Granek, Piotr Mieczkowski, Maria E Cardenas, Joseph Heitman
Calcineurin is a highly conserved Ca2+/calmodulin-dependent serine/threonine-specific protein phosphatase that orchestrates cellular Ca2+ signaling responses. In Cryptococcus neoformans, calcineurin is activated by multiple stresses including high temperature, and is essential for stress adaptation and virulence. The transcription factor Crz1 is a major calcineurin effector in Saccharomyces cerevisiae and other fungi. Calcineurin dephosphorylates Crz1, thereby enabling Crz1 nuclear translocation and transcription of target genes...
April 2017: PLoS Genetics
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
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