scholarly journals Phosphate in Virulence of Candida albicans and Candida glabrata

2020 ◽  
Vol 6 (2) ◽  
pp. 40 ◽  
Author(s):  
Julia R. Köhler ◽  
Maikel Acosta-Zaldívar ◽  
Wanjun Qi
Keyword(s):  
Stress Responses ◽  
Drug Targets ◽  
Fungal Pathogens ◽  
Essential Element ◽  
Close Relative ◽  
Pho Regulon ◽  
Phosphate Homeostasis ◽  
Yeast Saccharomyces Cerevisiae ◽  
Atp Production ◽  
Novel Drug

Candida species are the most commonly isolated invasive human fungal pathogens. A role for phosphate acquisition in their growth, resistance against host immune cells, and tolerance of important antifungal medications is becoming apparent. Phosphorus is an essential element in vital components of the cell, including chromosomes and ribosomes. Producing the energy currency of the cell, ATP, requires abundant inorganic phosphate. A comparison of the network of regulators and effectors that controls phosphate acquisition and intracellular distribution, the PHO regulon, between the model yeast Saccharomyces cerevisiae, a plant saprobe, its evolutionarily close relative C. glabrata, and the more distantly related C. albicans, highlights the need to coordinate phosphate homeostasis with adenylate biosynthesis for ATP production. It also suggests that fungi that cope with phosphate starvation as they invade host tissues, may link phosphate acquisition to stress responses as an efficient mechanism of anticipatory regulation. Recent work indicates that connections among the PHO regulon, Target of Rapamycin Complex 1 signaling, oxidative stress management, and cell wall construction are based both in direct signaling links, and in the provision of phosphate for sufficient metabolic intermediates that are substrates in these processes. Fundamental differences in fungal and human phosphate homeostasis may offer novel drug targets.

scholarly journals Acetylation-mediated phase control of the nucleolus regulates cellular acetyl-CoA responses

2020 ◽  
Author(s):  
Ryan Houston ◽  
Shiori Sekine ◽  
Michael J. Calderon ◽  
Fayaz Seifuddin ◽  
Guanghui Wang ◽  
...  
Keyword(s):  
Stress Responses ◽  
Culture Media ◽  
Lipid Synthesis ◽  
Essential Element ◽  
Cell System ◽  
Cellular Functions ◽  
Acetyl Coa ◽  
Atp Production ◽  
Wide Range ◽  
A Cell

SummaryThe metabolite acetyl-CoA serves as an essential element for a wide range of cellular functions including ATP production, lipid synthesis and protein acetylation. Intracellular acetyl-CoA concentrations are associated with nutrient availability, but the mechanisms by which a cell responds to fluctuations in acetyl-CoA levels remain elusive. Here, we generate a cell system to selectively manipulate the nucleo-cytoplasmic levels of acetyl-CoA using CRISPR-mediated gene editing and acetate supplementation of the culture media. Using this system and quantitative omics analyses, we demonstrate that acetyl-CoA depletion alters the integrity of the nucleolus, impairing ribosomal RNA synthesis and evoking the ribosomal protein-dependent activation of p53. This nucleolar remodeling appears to be mediated through the class IIa HDAC deacetylases regulating the phase state of the nucleolus. Our findings highlight acetylation-mediated control of the nucleolus as an important hub linking acetyl-CoA fluctuations to cellular stress responses.

scholarly journals Muscle Wasting Diseases: Novel Targets and Treatments

2019 ◽  
Vol 59 (1) ◽  
pp. 315-339 ◽  
Author(s):  
Regula Furrer ◽  
Christoph Handschin
Keyword(s):  
Skeletal Muscle ◽  
Drug Targets ◽  
Muscle Wasting ◽  
Current Knowledge ◽  
Essential Element ◽  
Well Being ◽  
Muscle Diseases ◽  
Muscle Plasticity ◽  
Muscle Tissues ◽  
Novel Drug

Adequate skeletal muscle plasticity is an essential element for our well-being, and compromised muscle function can drastically affect quality of life, morbidity, and mortality. Surprisingly, however, skeletal muscle remains one of the most under-medicated organs. Interventions in muscle diseases are scarce, not only in neuromuscular dystrophies, but also in highly prevalent secondary wasting pathologies such as sarcopenia and cachexia. Even in other diseases that exhibit a well-established risk correlation of muscle dysfunction due to a sedentary lifestyle, such as type 2 diabetes or cardiovascular pathologies, current treatments are mostly targeted on non-muscle tissues. In recent years, a renewed focus on skeletal muscle has led to the discovery of various novel drug targets and the design of new pharmacological approaches. This review provides an overview of the current knowledge of the key mechanisms involved in muscle wasting conditions and novel pharmacological avenues that could ameliorate muscle diseases.

scholarly journals Acetylation-mediated remodeling of the nucleolus regulates cellular acetyl-CoA responses

PLoS Biology ◽  
2020 ◽  
Vol 18 (11) ◽  
pp. e3000981
Author(s):  
Ryan Houston ◽  
Shiori Sekine ◽  
Michael J. Calderon ◽  
Fayaz Seifuddin ◽  
Guanghui Wang ◽  
...  
Keyword(s):  
Stress Responses ◽  
Histone Deacetylases ◽  
Culture Media ◽  
Lipid Synthesis ◽  
Essential Element ◽  
Cell System ◽  
Acetyl Coa ◽  
Atp Production ◽  
Wide Range ◽  
A Cell

The metabolite acetyl-coenzyme A (acetyl-CoA) serves as an essential element for a wide range of cellular functions including adenosine triphosphate (ATP) production, lipid synthesis, and protein acetylation. Intracellular acetyl-CoA concentrations are associated with nutrient availability, but the mechanisms by which a cell responds to fluctuations in acetyl-CoA levels remain elusive. Here, we generate a cell system to selectively manipulate the nucleo-cytoplasmic levels of acetyl-CoA using clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing and acetate supplementation of the culture media. Using this system and quantitative omics analyses, we demonstrate that acetyl-CoA depletion alters the integrity of the nucleolus, impairing ribosomal RNA synthesis and evoking the ribosomal protein-dependent activation of p53. This nucleolar remodeling appears to be mediated through the class IIa histone deacetylases (HDACs). Our findings highlight acetylation-mediated control of the nucleolus as an important hub linking acetyl-CoA fluctuations to cellular stress responses.

scholarly journals Regulation of the heat shock transcription factor Hsf1 in fungi: implications for temperature-dependent virulence traits

2018 ◽  
Vol 18 (5) ◽  
Author(s):  
Amanda O Veri ◽  
Nicole Robbins ◽  
Leah E Cowen
Keyword(s):  
Transcription Factor ◽  
Heat Shock ◽  
Stress Responses ◽  
Transcriptional Activation ◽  
Fungal Pathogens ◽  
Heat Shock Transcription Factor ◽  
Yeast Saccharomyces Cerevisiae ◽  
Virulence Traits ◽  
And Function ◽  
The Impact

Abstract The impact of fungal pathogens on human health is devastating. For fungi and other pathogens, a key determinant of virulence is the capacity to thrive at host temperatures, with elevated temperature in the form of fever as a ubiquitous host response to defend against infection. A prominent feature of cells experiencing heat stress is the increased expression of heat shock proteins (Hsps) that play pivotal roles in the refolding of misfolded proteins in order to restore cellular homeostasis. Transcriptional activation of this heat shock response is orchestrated by the essential heat shock transcription factor, Hsf1. Although the influence of Hsf1 on cellular stress responses has been studied for decades, many aspects of its regulation and function remain largely enigmatic. In this review, we highlight our current understanding of how Hsf1 is regulated and activated in the model yeast Saccharomyces cerevisiae, and highlight exciting recent discoveries related to its diverse functions under both basal and stress conditions. Given that thermal adaption is a fundamental requirement for growth and virulence in fungal pathogens, we also compare and contrast Hsf1 activation and function in other fungal species with an emphasis on its role as a critical regulator of virulence traits.

Novel drug targets in 2019

2020 ◽  
Vol 19 (5) ◽  
pp. 300-300 ◽  
Author(s):  
Sorin Avram ◽  
Liliana Halip ◽  
Ramona Curpan ◽  
Tudor I. Oprea
Keyword(s):  
Drug Targets ◽  
Novel Drug ◽  
Novel Drug Targets
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