scholarly journals N-acetylglucosamine Signaling: Transcriptional Dynamics of a Novel Sugar Sensing Cascade in a Model Pathogenic Yeast, Candida albicans

2021 ◽  
Vol 7 (1) ◽  
pp. 65
Author(s):  
Kongara Hanumantha Rao ◽  
Soumita Paul ◽  
Swagata Ghosh
Keyword(s):  
Candida Albicans ◽  
Transcriptional Response ◽  
Amino Sugar ◽  
Therapeutic Interventions ◽  
Gene Promoters ◽  
Catabolic Gene ◽  
Pathogenic Yeast ◽  
Cellular Processes ◽  
Transcriptional Dynamics ◽  
Recent Developments

The amino sugar, N-acetylglucosamine (GlcNAc), has emerged as an attractive messenger of signaling in the pathogenic yeast Candida albicans, given its multifaceted role in cellular processes, including GlcNAc scavenging, import and metabolism, morphogenesis (yeast to hyphae and white to opaque switch), virulence, GlcNAc induced cell death (GICD), etc. During signaling, the exogenous GlcNAc appears to adopt a simple mechanism of gene regulation by directly activating Ngs1, a novel GlcNAc sensor and transducer, at the chromatin level, to activate transcriptional response through the promoter acetylation. Ngs1 acts as a master regulator in GlcNAc signaling by regulating GlcNAc catabolic gene expression and filamentation. Ndt80-family transcriptional factor Rep1 appears to be involved in the recruitment of Ngs1 to GlcNAc catabolic gene promoters. For promoting filamentation, GlcNAc adopts a little modified strategy by utilizing a recently evolved transcriptional loop. Here, Biofilm regulator Brg1 takes up the key role, getting up-regulated by Ngs1, and simultaneously induces Hyphal Specific Genes (HSGs) expression by down-regulating NRG1 expression. GlcNAc kinase Hxk1 appears to play a prominent role in signaling. Recent developments in GlcNAc signaling have made C. albicans a model system to understand its role in other eukaryotes as well. The knowledge thus gained would assist in designing therapeutic interventions for the control of candidiasis and other fungal diseases.

scholarly journals Inhibitors of cellular signalling are cytotoxic or block the budded-to-hyphal transition in the pathogenic yeast Candida albicans

2009 ◽  
Vol 58 (6) ◽  
pp. 779-790 ◽  
Author(s):  
Kurt A. Toenjes ◽  
Benjamin C. Stark ◽  
Krista M. Brooks ◽  
Douglas I. Johnson
Keyword(s):  
Candida Albicans ◽  
Cell Biology ◽  
Mammalian Cells ◽  
Signalling Pathways ◽  
Pathogenic Yeast ◽  
Fungal Host ◽  
Cellular Processes ◽  
Localization Analysis ◽  
Inhibitory Molecules ◽  
G Protein Coupled

The pathogenic yeast Candida albicans can grow in multiple morphological states including budded, pseudohyphal and true hyphal forms. The ability to interconvert between budded and hyphal forms, herein termed the budded-to-hyphal transition (BHT), is important for C. albicans virulence, and is regulated by multiple environmental and cellular signals. To identify small-molecule inhibitors of known cellular processes that can also block the BHT, a microplate-based morphological assay was used to screen the BIOMOL–Institute of Chemistry and Cell Biology (ICCB) Known Bioactives collection from the ICCB-Longwood Screening Facility (Harvard Medical School, Boston, MA, USA). Of 480 molecules tested, 53 were cytotoxic to C. albicans and 16 were able to block the BHT without inhibiting budded growth. These 16 BHT inhibitors affected protein kinases, protein phosphatases, Ras signalling pathways, G protein-coupled receptors, calcium homeostasis, nitric oxide and guanylate cyclase signalling, and apoptosis in mammalian cells. Several of these molecules were also able to inhibit filamentous growth in other Candida species, as well as the pathogenic filamentous fungus Aspergillus fumigatus, suggesting a broad fungal host range for these inhibitory molecules. Results from secondary assays, including hyphal-specific transcription and septin localization analysis, were consistent with the inhibitors affecting known BHT signalling pathways in C. albicans. Therefore, these molecules will not only be invaluable in deciphering the signalling pathways regulating the BHT, but also may serve as starting points for potential new antifungal therapeutics.

scholarly journals Functional Roles of Bromodomain Proteins in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3606
Author(s):  
Samuel P. Boyson ◽  
Cong Gao ◽  
Kathleen Quinn ◽  
Joseph Boyd ◽  
Hana Paculova ◽  
...  
Keyword(s):  
Open Chromatin ◽  
Structural Domains ◽  
Pharmacological Agents ◽  
Functional Roles ◽  
Cellular Processes ◽  
Protein Interactome ◽  
Interaction Partners ◽  
Recent Developments ◽  
Bromodomain Proteins ◽  
Chromatin Configuration

Histone acetylation is generally associated with an open chromatin configuration that facilitates many cellular processes including gene transcription, DNA repair, and DNA replication. Aberrant levels of histone lysine acetylation are associated with the development of cancer. Bromodomains represent a family of structurally well-characterized effector domains that recognize acetylated lysines in chromatin. As part of their fundamental reader activity, bromodomain-containing proteins play versatile roles in epigenetic regulation, and additional functional modules are often present in the same protein, or through the assembly of larger enzymatic complexes. Dysregulated gene expression, chromosomal translocations, and/or mutations in bromodomain-containing proteins have been correlated with poor patient outcomes in cancer. Thus, bromodomains have emerged as a highly tractable class of epigenetic targets due to their well-defined structural domains, and the increasing ease of designing or screening for molecules that modulate the reading process. Recent developments in pharmacological agents that target specific bromodomains has helped to understand the diverse mechanisms that bromodomains play with their interaction partners in a variety of chromatin processes, and provide the promise of applying bromodomain inhibitors into the clinical field of cancer treatment. In this review, we explore the expression and protein interactome profiles of bromodomain-containing proteins and discuss them in terms of functional groups. Furthermore, we highlight our current understanding of the roles of bromodomain-containing proteins in cancer, as well as emerging strategies to specifically target bromodomains, including combination therapies using bromodomain inhibitors alongside traditional therapeutic approaches designed to re-program tumorigenesis and metastasis.

scholarly journals Bioactive Coatings with Ag-Camphorimine Complexes to Prevent Surface Colonization by the Pathogenic Yeast Candida albicans

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 638
Author(s):  
M. Joana F. Pinheiro ◽  
Joana P. Costa ◽  
Fernanda Marques ◽  
Nuno P. Mira ◽  
M. Fernanda N. N. Carvalho ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Medical Devices ◽  
Mammalian Cells ◽  
Surface Engineering ◽  
Pathogenic Yeast ◽  
Bioactive Coatings ◽  
Clinical Strains ◽  
Persistent Infections ◽  
Compound Q ◽  
Significant Step

Currently there is a gap between the rate of new antifungal development and the emergence of resistance among Candida clinical strains, particularly threatened by the extreme adhesiveness of C. albicans to indwelling medical devices. Two silver camphorimine complexes, [Ag(OH){OC10H14N(C6H4)2NC10H14O}] (compound P) and [{Ag(OC10H14NC6H4CH3-p)}2(μ-O)] (compound Q), are herein demonstrated as having high inhibiting activity towards the growth of Candida albicans and Candida glabrata clinical strains resistant to azoles, the frontline antifungals used in clinical practice. Compounds P and Q were also explored as bioactive coatings to prevent colonization by C. albicans and colonize the surface of indwelling medical devices, resulting in persistent infections. Functionalization of stainless steel with polycaprolactone (PCL) matrix embedded with compounds P or Q was reported for the first time to inhibit the colonization of C. albicans by 82% and 75%, respectively. The coating of PCL loaded with Q or P did not cause cytotoxic effects in mammalian cells, demonstrating the biocompatibility of the explored approach. The identification and further exploration of new approaches for surface engineering based on new molecules that can sensitize resistant strains, as herein demonstrated for complexes P and Q, is a significant step forward to improve the successful treatment of candidiasis.

scholarly journals Copper Availability Influences the Transcriptomic Response of Candida albicans to Fluconazole Stress

2021 ◽  
Vol 11 (4) ◽  
Author(s):  
Elizabeth W Hunsaker ◽  
Chen-Hsin Albert Yu ◽  
Katherine J Franz
Keyword(s):  
Candida Albicans ◽  
Time Course ◽  
Transcriptional Response ◽  
Metal Homeostasis ◽  
Metal Availability ◽  
Drug Induced ◽  
Transcriptomic Response ◽  
Opportunistic Fungal Pathogen ◽  
Whole Transcriptome Analysis ◽  
Whole Transcriptome

Abstract The ability of pathogens to maintain homeostatic levels of essential biometals is known to be important for survival and virulence in a host, which itself regulates metal availability as part of its response to infection. Given this importance of metal homeostasis, we sought to address how the availability of copper in particular impacts the response of the opportunistic fungal pathogen Candida albicans to treatment with the antifungal drug fluconazole. The present study reports whole transcriptome analysis via time-course RNA-seq of C. albicans cells exposed to fluconazole with and without 10 µM supplemental CuSO4 added to the growth medium. The results show widespread impacts of small changes in Cu availability on the transcriptional response of C. albicans to fluconazole. Of the 2359 genes that were differentially expressed under conditions of cotreatment, 50% were found to be driven uniquely by exposure to both Cu and fluconazole. The breadth of metabolic processes that were affected by cotreatment illuminates a fundamental intersectionality between Cu metabolism and fungal response to drug stress. More generally, these results show that seemingly minor fluctuations in Cu availability are sufficient to shift cells’ transcriptional response to drug stress. Ultimately, the findings may inform the development of new strategies that capitalize on drug-induced vulnerabilities in metal homeostasis pathways.

scholarly journals The Early Transcriptional Response of Human Granulocytes to Infection with Candida albicans Is Not Essential for Killing but Reflects Cellular Communications

2006 ◽  
Vol 75 (3) ◽  
pp. 1493-1501 ◽  
Author(s):  
Chantal Fradin ◽  
Abigail L. Mavor ◽  
Günther Weindl ◽  
Martin Schaller ◽  
Karin Hanke ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mononuclear Cells ◽  
De Novo ◽  
Transcriptional Response ◽  
Mononuclear Leukocytes ◽  
General Notion ◽  
Genes Encoding ◽  
Global Transcriptional Profile ◽  
Life Threatening ◽  
Systemic Infections

ABSTRACT Candida albicans is a polymorphic opportunistic fungus that can cause life-threatening systemic infections following hematogenous dissemination in patients susceptible to nosocomial infection. Neutrophils form part of the innate immune response, which is the first line of defense against microbes and is particularly important in C. albicans infections. To compare the transcriptional response of leukocytes exposed to C. albicans, we investigated the expression of key cytokine genes in polymorphonuclear and mononuclear leukocytes after incubation with C. albicans for 1 h. Isolated mononuclear cells expressed high levels of genes encoding proinflammatory signaling molecules, whereas neutrophils exhibited much lower levels, similar to those observed in whole blood. The global transcriptional profile of neutrophils was examined by using an immunology-biased human microarray to determine whether different morphological forms or the viability of C. albicans altered the transcriptome. Hyphal cells appeared to have the broadest effect, although the most strongly induced genes were regulated independently of morphology or viability. These genes were involved in proinflammatory cell-cell signaling, cell signal transduction, and cell growth. Generally, genes encoding known components of neutrophil granules showed no upregulation at this time point; however, lactoferrin, a well-known candidacidal peptide, was secreted by neutrophils. Addition to inhibitors of RNA or protein de novo synthesis did not influence the killing activity within 30 min. These results support the general notion that neutrophils do not require gene transcription to mount an immediate and direct attack against microbes. However, neutrophils exposed to C. albicans express genes involved in communication with other immune cells.

scholarly journals The Inflammatory Response Induced by Aspartic Proteases of Candida albicans Is Independent of Proteolytic Activity

2010 ◽  
Vol 78 (11) ◽  
pp. 4754-4762 ◽  
Author(s):  
Donatella Pietrella ◽  
Anna Rachini ◽  
Neelam Pandey ◽  
Lydia Schild ◽  
Mihai Netea ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Inflammatory Response ◽  
Proteolytic Activity ◽  
Necrosis Factor Alpha ◽  
Pathogenic Yeast ◽  
Aspartic Proteases ◽  
Akt Activation ◽  
Tnf Α ◽  
Factor Alpha ◽  
Pepstatin A

ABSTRACT The secretion of aspartic proteases (Saps) has long been recognized as a virulence-associated trait of the pathogenic yeast Candida albicans. In this study, we report that different recombinant Saps, including Sap1, Sap2, Sap3, and Sap6, have differing abilities to induce secretion of proinflammatory cytokines by human monocytes. In particular Sap1, Sap2, and Sap6 significantly induced interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), and IL-6 production. Sap3 was able to stimulate the secretion of IL-1β and TNF-α. All Saps tested were able to induce Ca2+ influx in monocytes. Treatment of these Saps with pepstatin A did not have any effect on cytokine secretion, indicating that their stimulatory potential was independent from their proteolytic activity. The capacity of Saps to induce inflammatory cytokine production was also independent from protease-activated receptor (PAR) activation and from the optimal pH for individual Sap activity. The interaction of Saps with monocytes induced Akt activation and phosphorylation of IκBα, which mediates translocation of NF-κB into the nucleus. Overall, these results suggest that individual Sap proteins can induce an inflammatory response and that this phenomenon is independent from the pH of a specific host niche and from Sap enzymatic activity. The inflammatory response is partially dependent on Sap denaturation and is triggered by the Akt/NF-κB activation pathway. Our data suggest a novel, activity-independent aspect of Saps during interactions of C. albicans with the host.

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