scholarly journals The Genomic Landscape of the Fungus-Specific SWI/SNF Complex Subunit, Snf6, in Candida albicans

mSphere ◽  
2017 ◽  
Vol 2 (6) ◽  
Author(s):  
Faiza Tebbji ◽  
Yaolin Chen ◽  
Adnane Sellam ◽  
Malcolm Whiteway
Keyword(s):  
Candida Albicans ◽  
Chromatin Remodeling ◽  
Opportunistic Pathogen ◽  
Resistance Mechanisms ◽  
Phenotypic Data ◽  
Content Type ◽  
Chromatin Remodeling Complex ◽  
Clinical Resistance ◽  
Immunosuppressed Patients

ABSTRACT Candida albicans is a natural component of the human microbiota but also an opportunistic pathogen that causes life-threatening infections in immunosuppressed patients. Current therapeutics include a limited number of molecules that suffer from limitations, including growing clinical resistance and toxicity. New molecules are being clinically investigated; however, the majority of these potential antifungals target the same processes as do the standard antifungals and might confront the same problems of toxicity and loss of efficiency due to the common resistance mechanisms. Here, we characterized the role of Snf6, a fungus-specific subunit of the chromatin-remodeling complex SWI/SNF. Our genomic and phenotypic data demonstrated a central role of Snf6 in biological processes that are critical for a fungal pathogen to colonize its host and cause disease, suggesting Snf6 as a possible antifungal target. SWI/SNF is an ATP-dependent chromatin-remodeling complex that is required for the regulation of gene expression in eukaryotes. While most of the fungal SWI/SNF components are evolutionarily conserved with those of the metazoan SWI/SNF, subunits such as Snf6 are specific to certain fungi and thus represent potential antifungal targets. We have characterized the role of the Snf6 protein in Candida albicans. Our data showed that although there was low conservation of its protein sequence with other fungal orthologs, Snf6 was copurified with bona fide SWI/SNF complex subunits. The role of Snf6 in C. albicans was investigated by determining its genome-wide occupancy using chromatin immunoprecipitation coupled to tiling arrays in addition to transcriptional profiling of the snf6 conditional mutant. Snf6 directs targets that were enriched in functions related to carbohydrate and amino acid metabolic circuits, to cellular transport, and to heat stress responses. Under hypha-promoting conditions, Snf6 expanded its set of targets to include promoters of genes related to respiration, ribosome biogenesis, mating, and vesicle transport. In accordance with the genomic occupancy data, an snf6 doxycycline-repressible mutant exhibited growth defects in response to heat stress and also when grown in the presence of different fermentable and nonfermentable carbon sources. Snf6 was also required to differentiate invasive hyphae in response to different cues. This study represents the first comprehensive characterization, at the genomic level, of the role of SWI/SNF in the pathogenic yeast C. albicans and uncovers functions that are essential for fungal morphogenesis and metabolic flexibility. IMPORTANCE Candida albicans is a natural component of the human microbiota but also an opportunistic pathogen that causes life-threatening infections in immunosuppressed patients. Current therapeutics include a limited number of molecules that suffer from limitations, including growing clinical resistance and toxicity. New molecules are being clinically investigated; however, the majority of these potential antifungals target the same processes as do the standard antifungals and might confront the same problems of toxicity and loss of efficiency due to the common resistance mechanisms. Here, we characterized the role of Snf6, a fungus-specific subunit of the chromatin-remodeling complex SWI/SNF. Our genomic and phenotypic data demonstrated a central role of Snf6 in biological processes that are critical for a fungal pathogen to colonize its host and cause disease, suggesting Snf6 as a possible antifungal target.

scholarly journals Critical role of Brg1 member of the SWI/SNF chromatin remodeling complex during neurogenesis and neural crest induction in zebrafish

2006 ◽  
Vol 235 (10) ◽  
pp. 2722-2735 ◽  
Author(s):  
Binnur Eroglu ◽  
Guanghu Wang ◽  
Naxin Tu ◽  
Xutong Sun ◽  
Nahid F. Mivechi
Keyword(s):  
Neural Crest ◽  
Chromatin Remodeling ◽  
Critical Role ◽  
Chromatin Remodeling Complex

scholarly journals Role of Matrix β-1,3 Glucan in Antifungal Resistance of Non-albicans Candida Biofilms

2013 ◽  
Vol 57 (4) ◽  
pp. 1918-1920 ◽  
Author(s):  
K. F. Mitchell ◽  
H. T. Taff ◽  
M. A. Cuevas ◽  
E. L. Reinicke ◽  
H. Sanchez ◽  
...  
Keyword(s):  
Health Care ◽  
Drug Resistance ◽  
Candida Albicans ◽  
Care Setting ◽  
Antifungal Susceptibility ◽  
Antifungal Drug ◽  
Content Type ◽  
The Matrix ◽  
Biofilm Matrix

ABSTRACTCandidabiofilm infections pose an increasing threat in the health care setting due to the drug resistance associated with this lifestyle. Several mechanisms underlie the resistance phenomenon. InCandida albicans, one mechanism involves drug impedance by the biofilm matrix linked to β-1,3 glucan. Here, we show this is important for otherCandidaspp. We identified β-1,3 glucan in the matrix, found that the matrix sequesters antifungal drug, and enhanced antifungal susceptibility with matrix β-1,3 glucan hydrolysis.

scholarly journals Nucleotide Excision Repair Protein Rad23 Regulates Cell Virulence Independent of Rad4 in Candida albicans

mSphere ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Jia Feng ◽  
Shuangyan Yao ◽  
Yansong Dong ◽  
Jing Hu ◽  
Malcolm Whiteway ◽  
...  
Keyword(s):  
Dna Damage ◽  
Candida Albicans ◽  
Nucleotide Excision Repair ◽  
Dna Damage Response ◽  
Excision Repair ◽  
Content Type ◽  
Virulence Regulation ◽  
Nucleotide Excision ◽  
Damage Response

ABSTRACT In the pathogenic yeast Candida albicans, the DNA damage response contributes to pathogenicity by regulating cell morphology transitions and maintaining survival in response to DNA damage induced by reactive oxygen species (ROS) in host cells. However, the function of nucleotide excision repair (NER) in C. albicans has not been extensively investigated. To better understand the DNA damage response and its role in virulence, we studied the function of the Rad23 nucleotide excision repair protein in detail. The RAD23 deletion strain and overexpression strain both exhibit UV sensitivity, confirming the critical role of RAD23 in the nucleotide excision repair pathway. Genetic interaction assays revealed that the role of RAD23 in the UV response relies on RAD4 but is independent of RAD53, MMS22, and RAD18. RAD4 and RAD23 have similar roles in regulating cell morphogenesis and biofilm formation; however, only RAD23, but not RAD4, plays a negative role in virulence regulation in a mouse model. We found that the RAD23 deletion strain showed decreased survival in a Candida-macrophage interaction assay. Transcriptome sequencing (RNA-seq) and quantitative real-time PCR (qRT-PCR) data further revealed that RAD23, but not RAD4, regulates the transcription of a virulence factor, SUN41, suggesting a unique role of RAD23 in virulence regulation. Taking these observations together, our work reveals that the RAD23-related nucleotide excision pathway plays a critical role in the UV response but may not play a direct role in virulence. The virulence-related role of RAD23 may rely on the regulation of several virulence factors, which may give us further understanding about the linkage between DNA damage repair and virulence regulation in C. albicans. IMPORTANCE Candida albicans remains a significant threat to the lives of immunocompromised people. An understanding of the virulence and infection ability of C. albicans cells in the mammalian host may help with clinical treatment and drug discovery. The DNA damage response pathway is closely related to morphology regulation and virulence, as well as the ability to survive in host cells. In this study, we checked the role of the nucleotide excision repair (NER) pathway, the key repair system that functions to remove a large variety of DNA lesions such as those caused by UV light, but whose function has not been well studied in C. albicans. We found that Rad23, but not Rad4, plays a role in virulence that appears independent of the function of the NER pathway. Our research revealed that the NER pathway represented by Rad4/Rad23 may not play a direct role in virulence but that Rad23 may play a unique role in regulating the transcription of virulence genes that may contribute to the virulence of C. albicans.

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

2014 ◽  
Vol 13 (12) ◽  
pp. 1557-1566 ◽  
Author(s):  
Shen-Huan Liang ◽  
Jen-Hua Cheng ◽  
Fu-Sheng Deng ◽  
Pei-An Tsai ◽  
Ching-Hsuan Lin
Keyword(s):  
Candida Albicans ◽  
Protein Kinase ◽  
Synthetic Medium ◽  
Opportunistic Pathogen ◽  
Phenotypic Switch ◽  
Content Type ◽  
Host Interactions ◽  
Main Pathway ◽  
Phenotypic Transition ◽  
External Stimuli

ABSTRACTCandida albicansis 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 understandingC. albicansbehavior is the white-opaque 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, andN-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 inC. albicans. In this work, we first show that loss of theHOG1gene ina/aand α/α cells, but nota/α cells, results in 100% white-to-opaque switching when cells are grown on synthetic medium, indicating that switching is repressed by thea1/α2 heterodimer that repressesWOR1gene expression. Indeed, switching in thehog1Δ strain was dependent on the presence ofWOR1, as ahog1Δwor1Δ strain did not show switching to the opaque state. Deletion ofPBS2andSSK2also resulted inC. albicanscells 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 inC. albicans.

scholarly journals The role of the SWI/SNF chromatin remodeling complex in pancreatic ductal adenocarcinoma

2020 ◽  
Author(s):  
Motoyuki Tsuda ◽  
Akihisa Fukuda ◽  
Munenori Kawai ◽  
Osamu Araki ◽  
Hiroshi Seno
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Chromatin Remodeling ◽  
Ductal Adenocarcinoma ◽  
Chromatin Remodeling Complex

scholarly journals Role of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Joanna Cyrta ◽  
Anke Augspach ◽  
Maria Rosaria De Filippo ◽  
Davide Prandi ◽  
Phillip Thienger ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Chromatin Remodeling ◽  
Hormonal Treatment ◽  
Prostate Adenocarcinoma ◽  
Aggressive Disease ◽  
Chromatin Remodeling Complex ◽  
Large Patient ◽  
Neuroendocrine Prostate Cancer ◽  
Specific Factors

Abstract Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in around 10–20% of these patients is lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data point to a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may also be relevant for other solid tumors.

scholarly journals Aspergillus fumigatus Intrinsic Fluconazole Resistance Is Due to the Naturally Occurring T301I Substitution in Cyp51Ap

2016 ◽  
Vol 60 (9) ◽  
pp. 5420-5426 ◽  
Author(s):  
Florencia Leonardelli ◽  
Daiana Macedo ◽  
Catiana Dudiuk ◽  
Matias S. Cabeza ◽  
Soledad Gamarra ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Aspergillus Fumigatus ◽  
Parental Strain ◽  
Amino Acid Residues ◽  
Intrinsic Resistance ◽  
Single Nucleotide ◽  
Fluconazole Resistance ◽  
Content Type ◽  
Natural Polymorphism

ABSTRACTAspergillus fumigatusintrinsic fluconazole resistance has been demonstrated to be linked to theCYP51Agene, although the precise molecular mechanism has not been elucidated yet. Comparisons betweenA. fumigatusCyp51Ap andCandida albicansErg11p sequences showed differences in amino acid residues already associated with fluconazole resistance inC. albicans. The aim of this study was to analyze the role of the natural polymorphism I301 inAspergillus fumigatusCyp51Ap in the intrinsic fluconazole resistance phenotype of this pathogen. The I301 residue inA. fumigatusCyp51Ap was replaced with a threonine (analogue to T315 atCandida albicansfluconazole-susceptible Erg11p) by changing one single nucleotide in theCYP51Agene. Also, aCYP51Aknockout strain was obtained using the same parental strain. Both mutants' antifungal susceptibilities were tested. The I301T mutant exhibited a lower level of resistance to fluconazole (MIC, 20 μg/ml) than the parental strain (MIC, 640 μg/ml), while no changes in MIC were observed for other azole- and non-azole-based drugs. These data strongly implicate theA. fumigatusCyp51Ap I301 residue in the intrinsic resistance to fluconazole.

scholarly journals Identification of a Cell Death Pathway in Candida albicans during the Response to Pheromone

2010 ◽  
Vol 9 (11) ◽  
pp. 1690-1701 ◽  
Author(s):  
Kevin Alby ◽  
Dana Schaefer ◽  
Racquel Kim Sherwood ◽  
Stephen K. Jones ◽  
Richard J. Bennett
Keyword(s):  
Cell Death ◽  
Candida Albicans ◽  
Laboratory Strain ◽  
Opportunistic Pathogen ◽  
Cell Types ◽  
Yeast Cells ◽  
Phenotypic Switching ◽  
Morphological Response ◽  
Content Type ◽  
Cell Death Pathway

ABSTRACT Mating in hemiascomycete yeasts involves the secretion of pheromones that induce sexual differentiation in cells of the opposite mating type. Studies in Saccharomyces cerevisiae have revealed that a subpopulation of cells experiences cell death during exposure to pheromone. In this work, we tested whether the phenomenon of pheromone-induced death (PID) also occurs in the opportunistic pathogen Candida albicans. Mating in C. albicans is uniquely regulated by white-opaque phenotypic switching; both cell types respond to pheromone, but only opaque cells undergo the morphological transition and cell conjugation. We show that approximately 20% of opaque cells, but not white cells, of laboratory strain SC5314 experience pheromone-induced death. Furthermore, analysis of mutant strains revealed that PID was significantly reduced in strains lacking Fig1 or Fus1 transmembrane proteins that are induced during the mating process and, we now show, are necessary for efficient mating in C. albicans. The level of PID was also Ca2+ dependent, as chelation of Ca2+ ions increased cell death to almost 50% of the population. However, in contrast to S. cerevisiae PID, pheromone-induced killing of C. albicans cells was largely independent of signaling via the Ca2+-dependent protein phosphatase calcineurin, even when combined with the loss of Cmk1 and Cmk2 proteins. Finally, we demonstrate that levels of PID vary widely between clinical isolates of C. albicans, with some strains experiencing close to 70% cell death. We discuss these findings in light of the role of prodeath and prosurvival pathways operating in yeast cells undergoing the morphological response to pheromone.

scholarly journals Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

2017 ◽  
Vol 86 (2) ◽  
Author(s):  
Angelique N. Besold ◽  
Benjamin A. Gilston ◽  
Jana N. Radin ◽  
Christian Ramsoomair ◽  
Edward M. Culbertson ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Stress Responses ◽  
Metal Binding ◽  
Content Type ◽  
Nutritional Immunity ◽  
Numerous Cell ◽  
Transcriptional Changes ◽  
Opportunistic Fungal Pathogen ◽  
First Time

ABSTRACT The opportunistic fungal pathogen Candida albicans acquires essential metals from the host, yet the host can sequester these micronutrients through a process known as nutritional immunity. How the host withholds metals from C. albicans has been poorly understood; here we examine the role of calprotectin (CP), a transition metal binding protein. When CP depletes bioavailable Zn from the extracellular environment, C. albicans strongly upregulates ZRT1 and PRA1 for Zn import and maintains constant intracellular Zn through numerous cell divisions. We show for the first time that CP can also sequester Cu by binding Cu(II) with subpicomolar affinity. CP blocks fungal acquisition of Cu from serum and induces a Cu starvation stress response involving SOD1 and SOD3 superoxide dismutases. These transcriptional changes are mirrored when C. albicans invades kidneys in a mouse model of disseminated candidiasis, although the responses to Cu and Zn limitations are temporally distinct. The Cu response progresses throughout 72 h, while the Zn response is short-lived. Notably, these stress responses were attenuated in CP null mice, but only at initial stages of infection. Thus, Zn and Cu pools are dynamic at the host-pathogen interface and CP acts early in infection to restrict metal nutrients from C. albicans.

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