Titan cells formation in Cryptococcus neoformans is finely tuned by environmental conditions and modulated by positive and negative genetic regulators

PLoS Pathogens, Journal Year: 2018, Volume and Issue: 14(5), P. e1006982 - e1006982

Published: May 18, 2018

The pathogenic fungus Cryptococcus neoformans exhibits morphological changes in cell size during lung infection, producing both typical 5 to 7 μm cells and large titan (> 10 up 100 μm). We found optimized vitro conditions that produce order identify the ancestry of cells, environmental determinants, key gene regulators formation. Titan generated harbor main characteristics produced vivo including their (>10 μm), polyploidy with a single nucleus, vacuole, dense capsule, thick wall. Here we show derived from enlargement progenitor population independent yeast growth rate. Change incubation medium, hypoxia, nutrient starvation low pH were factors trigger formation, while quorum sensing like initial inoculum concentration, pantothenic acid, peptide Qsp1p also impacted Inhibition ergosterol, protein nucleic acid biosynthesis altered as did serum, phospholipids anti-capsular antibodies our settings. explored genetic important for formation using three approaches. Using H99-derivative strains natural differences, showed was dependent on LMP1 SGF29 genes. By screening deletion collection, confirmed GPR4/5-RIM101, CAC1 genes required generate PKR1, TSP2, USV101 negatively regulated Furthermore, analysis spontaneous Pkr1 loss-of-function clinical isolates role negative regulator Through development standardized robust assay, results provide new insights into biogenesis identification multiple factors/pathways.

Language: Английский

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Mechanisms and Therapeutic Implications of GSK-3 in Treating Neurodegeneration

Cells, Journal Year: 2021, Volume and Issue: 10(2), P. 262 - 262

Published: Jan. 29, 2021

Neurodegenerative disorders are spreading worldwide and one of the greatest threats to public health. There is currently no adequate therapy for these disorders, therefore there an urgent need accelerate discovery development effective treatments. Although neurodegenerative broad ranging highly complex, they may share overlapping mechanisms, thus potentially manifest common targets therapeutic interventions. Glycogen synthase kinase-3 (GSK-3) now acknowledged be a central player in regulating mood behavior, cognitive functions, neuron viability. Indeed, many controlled by GSK-3 critically involved progressing deterioration disease pathogenesis. In this review, we focus on three pathways that represent prominent mechanisms linking with disorders: cytoskeleton organization, mammalian target rapamycin (mTOR)/autophagy axis, mitochondria. We also consider challenges opportunities inhibitors treating neurodegeneration.

Language: Английский

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Lipid metabolism research in oleaginous fungus Mortierella alpina: Current progress and future prospects

Biotechnology Advances, Journal Year: 2021, Volume and Issue: 54, P. 107794 - 107794

Published: July 8, 2021

Language: Английский

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Non-dikarya fungi share the TORC1 pathway with animals, not with Saccharomyces cerevisiae

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 18, 2025

Abstract Target of rapamycin (TOR), discovered in Saccharomyces cerevisiae , is a highly conserved serine/threonine kinase acting as regulatory hub between the cell and its environment. Like mammals, fungi, TOR complex 1 (TORC1) pathway essential for coordinating growth response to nutrient availability. The activation TORC1 similar yeast while inhibition more mammals. This divergence regulation opens question how common are mammalian variants fungal kingdom. In this work, we trace evolutionary history components throughout Our findings show that these fungi contain mammalian-specific KICSTOR inhibition. They also possess orthologs serine, arginine methionine sensors orchestrate starvation Rheb-TSC mediated was lost Saccharomycotina non-Dikarya. These indicate non-Dikarya resembles TORC1. many inhibitory evolved alternate mechanisms. Furthermore, our work highlights limitations using S. model putting forward other possible research models.

Language: Английский

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On the duration of the microbial lag phase

Current Genetics, Journal Year: 2019, Volume and Issue: 65(3), P. 721 - 727

Published: Jan. 21, 2019

When faced with environmental changes, microbes enter a lag phase during which cell growth is arrested, allowing cells to adapt the new situation. The discovery of started field gene regulation and led unraveling underlying mechanisms. However, factors determining exact duration dynamics remain largely elusive. Naively, one would expect that as quickly possible, so they can resume compete other organisms. recent studies show last from several hours up days. Moreover, some within same population take much longer than others, despite being genetically identical. In addition, also influenced by past, exposure given environment leading quicker adaptation when returns. Genome-wide screens in Saccharomyces cerevisiae on carbon source shifts now suggest length phase, heterogeneity times individual cells, history-dependent behavior are not determined time it takes induce few specific genes related uptake metabolism source. Instead, major shift general metabolism, particular switch between fermentation respiration, bottleneck determines duration. This suggests there may be fitness trade-off complete cell's environment, short changes.

Language: Английский

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Cellular quiescence in budding yeast

Yeast, Journal Year: 2020, Volume and Issue: 38(1), P. 12 - 29

Published: Dec. 22, 2020

Abstract Cellular quiescence, the temporary and reversible exit from proliferative growth, is predominant state of all cells. However, our understanding biological processes molecular mechanisms that underlie cell quiescence remains incomplete. As with mitotic cycle, budding fission yeast are preeminent model systems for studying cellular owing to their rich experimental toolboxes evolutionary conservation across eukaryotes pathways control quiescence. Here, we review current knowledge in how it pertains other organisms, including multicellular animals. Quiescence entails large‐scale remodeling virtually every process, organelle, gene expression, metabolic executed dynamically as cells undergo initiation, maintenance, We these major transitions, bases, highlight unresolved questions. summarize primary methods employed studies discuss relative merits. Understanding has important consequences human disease quiescent single‐celled microbes notoriously difficult kill play roles diseases such cancer. argue research on will be accelerated through adoption common criteria, methods, defining An integrated approach a focus behavior individual cells, yield new insights into leading more complete life cycle Take Away Quiescent viable have reversibly exited induced response variety nutrient starvation signals three phases: organelles, metabolism Single‐cell approaches required address heterogeneity among

Language: Английский

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In-depth understanding of molecular mechanisms of aldehyde toxicity to engineer robust Saccharomyces cerevisiae

Applied Microbiology and Biotechnology, Journal Year: 2021, Volume and Issue: 105(7), P. 2675 - 2692

Published: March 20, 2021

Language: Английский

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Build-UPS and break-downs: metabolism impacts on proteostasis and aging

Cell Death and Differentiation, Journal Year: 2021, Volume and Issue: 28(2), P. 505 - 521

Published: Jan. 4, 2021

Abstract Perturbation of metabolism elicits cellular stress which profoundly modulates the proteome and thus protein homeostasis (proteostasis). Consequently, changes in due to metabolic shift require adaptive mechanisms by molecular quality control. The vitally controlling proteostasis embrace entire life cycle a involving translational control at ribosome, chaperone-assisted native folding, subcellular sorting as well proteolysis proteasome or autophagy. While imbalance decline have been recognized hallmarks aging age-associated diseases, both processes are largely considered independently. Here, we delineate how stability is governed insulin/IGF1 signaling (IIS), mechanistic target Rapamycin (TOR), 5′ adenosine monophosphate-activated kinase (AMPK), NAD-dependent deacetylases (Sir2-like proteins known sirtuins). This comprehensive overview emphasizing regulatory interconnection between central pathways proteostasis, indicating relevance shared nodes targets for future therapeutic interventions.

Language: Английский

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Genetic effects on molecular network states explain complex traits

Molecular Systems Biology, Journal Year: 2023, Volume and Issue: 19(8)

Published: July 24, 2023

Abstract The complexity of many cellular and organismal traits results from the integration genetic environmental factors via molecular networks. Network structure effect propagation are best understood at level functional modules, but so far, no concept has been established to include global network state. Here, we show when how perturbations lead changes that confined small parts a versus they modulation states. Integrating multi‐omics profiling genetically heterogeneous budding fission yeast strains with an array identified central state transition is related PKA TOR ( PT ) signaling. Genetic variants affecting this globally shifted along single‐dimensional axis, thereby modulating processes including energy amino acid metabolism, transcription, translation, cell cycle control, stress response. We propose effects can propagate through large networks because requirement centrally coordinate activity fundamental processes.

Language: Английский

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A wake‐up call to quiescent cancer cells – potential use of DYRK1B inhibitors in cancer therapy

FEBS Journal, Journal Year: 2017, Volume and Issue: 285(7), P. 1203 - 1211

Published: Nov. 29, 2017

Nondividing cancer cells are relatively resistant to chemotherapeutic drugs and environmental stress factors. Promoting cell cycle re-entry of quiescent is a potential strategy enhance the cytotoxicity agents that target cycling cells. It therefore important elucidate mechanisms by which these maintained in state. The protein kinase dual specificity tyrosine phosphorylation-regulated 1B (DYRK1B) overexpressed subset cancers maintains cellular quiescence counteracting G0 /G1 -S phase transition. Specifically, DYRK1B controls S checkpoint stabilizing cyclin-dependent (CDK) inhibitor p27Kip1 inducing degradation cyclin D. also stabilizes DREAM complex represses gene expression arrested In addition, enhances survival upregulating antioxidant reducing intracellular levels reactive oxygen species (ROS). Substantial evidence indicates depletion or inhibition drives apoptosis those with high DYRK1B. Furthermore, small molecule inhibitors sensitize cytotoxic effects anticancer proliferating These encouraging findings justify continued efforts investigate use disrupt state overturn chemoresistance noncycling

Language: Английский

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