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Candida albicans; exploring glycosylation pathway in the search of targets for antimicrobial agents and yeast to hyphae transition
Get PDFMicrobial cell wall is mostly synthesized by the glycosylated proteins with the distinct
enzymatic activity. In this review we have concentrated on the description of the certain
steps of glycosylation and their effect on the cell wall integrity and yeast to hyphae
transition, the process enhancing the pathogenic properties of C.albicans.
The glycoproteins play an invaluable role in C. albicans virulence and they modulate
adhesive, invasive, morphogenetic and immune stimulating properties of the pathogen as
well as its susceptibility to the antifungal agents. Therefore, understanding of C. albicans
glycobiology might let us expand the arsenal in the war against fungal enemies. The
early stages of N-, O-glycans and GPI-anchor synthesis requires dolichol - the lipid
carrier of sugar residues. Diminished supply of dolichol causes series of defects in C.
albicans cells, among which aberrant protein glycosylation is the most evident.
Furthermore, the relations between the cell wall composition and integrity, resistance to
some antifungal and cell wall disturbing agents and dolichol dependent glycosylation are
observed. Moreover relevance of these reactions for the morphological differentiation of
C.albicans is described
BRM: the core ATPase subunit of SWI/SNF chromatin-remodelling complex—a tumour suppressor or tumour-promoting factor?
Get PDFBRM (BRAHMA) is a core, SWI2/SNF2-type ATPase subunit of SWI/SNF chromatin-remodelling complex (CRC) involved
in various important regulatory processes including development. Mutations in SMARCA2, a BRM-encoding gene
as well as overexpression or epigenetic silencing were found in various human diseases including cancer. Missense
mutations in SMARCA2 gene were recently connected with occurrence of Nicolaides–Baraitser genetics syndrome.
By contrast, SMARCA2 duplication rather than mutations is characteristic for Cofn–Siris syndrome. It is believed that
BRM usually acts as a tumour suppressor or a tumour susceptibility gene. However, other studies provided evidence
that BRM function may difer depending on the cancer type and the disease stage, where BRM may play a role in the
disease progression. The existence of alternative splicing forms of SMARCA2 gene, leading to appearance of truncated
functional, loss of function or gain-of-function forms of BRM protein suggest a far more complicated mode of BRMcontaining SWI/SNF CRCs actions. Therefore, the summary of recent knowledge regarding BRM alteration in various
types of cancer and highlighting of diferences and commonalities between BRM and BRG1, another SWI2/SNF2 type
ATPase, will lead to better understanding of SWI/SNF CRCs function in cancer development/progression. BRM has
been recently proposed as an attractive target for various anticancer therapies including the use of small molecule
inhibitors, synthetic lethality induction or proteolysis-targeting chimera (PROTAC). However, such attempts have some
limitations and may lead to severe side efects given the homology of BRM ATPase domain to other ATPases, as well as
due to the tissue-specifc appearance of BRM- and BRG1-containing SWI/SNF CRC classes. Thus, a better insight into
BRM-containing SWI/SNF CRCs function in human tissues and cancers is clearly required to provide a solid basis for
establishment of new safe anticancer therapies
Combined in silico and 19F NMR analysis of 5-fluorouracil metabolism in yeast at low ATP conditions.
Get PDFThe cytotoxic effect of 5-fluorouracil (5-FU) on yeast cells is thought to be mainly via a misincorporation of fluoropyrimidines into both RNA and DNA, not only DNA damage via inhibition of thymidylate synthase (TYMS) by fluorodeoxyuridine monophosphate (FdUMP). However, some studies on Saccharomyces cerevisiae show a drastic decrease in ATP concentration under oxidative stress, together with a decrease in concentration of other tri- and diphosphates. This raises a question if hydrolysis of 5-fluoro-2-deoxyuridine diphosphate (FdUDP) under oxidative stress could not lead to the presence of FdUMP and the activation of so-called ‘thymine-less death’ route. We attempted to answer this question with in silico modeling of 5-FU metabolic pathways, based on new experimental results, where the stages of intracellular metabolism of 5-FU in Saccharomyces cerevisiae were tracked by a combination of 19F and 31P NMR spectroscopic study. We have identified 5-FU, its nucleosides and nucleotides, and subsequent di- and/or triphosphates. Additionally, another wide 19F signal, assigned to fluorinated unstructured short RNA, has been also identified in the spectra. The concentration of individual metabolites was found to vary substantially within hours,however,theinitialsteady-statewaspreservedonlyforanhour,untiltheATPconcentration dropped by a half, which was monitored independently via 31P NMR spectra. After that, the catabolic process leading from triphosphates through monophosphates and nucleosides back to 5-FU was observed. These results imply careful design and interpretation of studies in 5-FU metabolism in yeast
Mitochondrial stress-dependent regulation of cellular protein synthesis
Get PDFThe production of newly synthesized proteins is vital for all cellular functions and is a determinant of cell growth and proliferation. The synthesis of polypeptide chains from mRNA molecules requires sophisticated machineries and mechanisms that need to be tightly regulated, and adjustable to current needs of the cell. Failures in the regulation of translation contribute to the loss of protein homeostasis, which can have deleterious effects on cellular function and organismal health. Unsurprisingly, the regulation of translation appears to be a crucial element in stress response mechanisms. This review provides an overview of mechanisms that modulate cytosolic protein synthesis upon cellular stress, with a focus on the attenuation of translation in response to mitochondrial stress. We then highlight links between mitochondrion-derived reactive oxygen species and the attenuation of reversible cytosolic translation through the oxidation of ribosomal proteins at their cysteine residues. We also discuss emerging concepts of how cellular mechanisms to stress are adapted, including the existence of alternative ribosomes and stress granules, and the regulation of co-translational import upon organelle stress
His6, His13, and His14 residues in Aβ 1–40 peptide significantly and specifically affect oligomeric equilibria
Get PDFOligomers of Aβ peptide are implicated as the most probable causative agent in Alzheimer’s disease. However, their structural properties remain elusive due to the dynamic and heterogeneous character of oligomeric species coexisting in solution. Nevertheless, new approaches, mainly based on mass spectrometry, provide unique access to these different structural forms. Using these methods, we previously showed that the N-terminal, non-amyloidogenic region of Aβ is involved in the network of interactions specifically stabilizing oligomers. In the present study, we identified three histidine residues as active participants in this network. Detailed knowledge of the structural features that are potentially important for oligomer-mediated neurotoxicity is a prerequisite for the rational design of oligomerization modifiers
Enhanced oligomerization of full-length RAGE by synergy of the interaction of its domains
Get PDFThe pattern recognition receptor RAGE (receptor for advanced glycation end-products) transmits proinflammatory signals in several inflammation-related pathological states, including vascular diseases, cancer, neurodegeneration and diabetes. Its oligomerization is believed to be important in signal transduction, but RAGE oligomeric structures and stoichiometries remain unclear. Different oligomerization modes have been proposed in studies involving different truncated versions of the extracellular parts of RAGE. Here, we provide basic characterization of the oligomerization patterns of full-length RAGE (including the transmembrane (TM) and cytosolic regions) and compare the results with oligomerization modes of its four truncated fragments. For this purpose, we used native mass spectrometry, analytical ultracentrifugation, and size-exclusion chromatography coupled with multi-angle light scattering. Our results confirm known oligomerization tendencies of separate domains and highlight the enhanced oligomerization properties of full-length RAGE. Mutational analyses within the GxxxG motif of the TM region show sensitivity of oligomeric distributions to the TM sequence. Using hydrogen-deuterium exchange, we mapped regions involved in TM-dependent RAGE oligomerization. Our data provide experimental evidence for the major role of the C2 and TM domains in oligomerization, underscoring synergy among different oligomerization contact regions along the RAGE sequence. These results also explain the variability of obtained oligomerization modes in RAGE fragments
Yeast-model-based study identified myosin- and calcium-dependent calmodulin signalling as a potential target for drug intervention in chorea-acanthocytosis
Get PDFHow cyclophosphamide at environmentally relevant concentration influences Daphnia magna life history and its proteome
Get PDFThe waste of commonly used medicines is known to contaminate freshwater ecosystems. Pharmaceuticals can be toxic, mutagenic, or modifying to freshwater organisms even at low concentrations if consider their permanent presence in the environment. Chemotherapeutics used to treat cancer, and in particular alkylating agents, contribute significantly to this form of pollution, the latter introducing cytotoxic and/or mutagenic lesions to the DNA and RNA of organisms which can be disruptive to their cells. The aim of the present study was to investigate the influence of the alkylating anticancer agent cyclophosphamide (CP) on Daphnia magna clones. We evaluated the life history parameters and protein profiles of this crustacean following exposure to environmentally relevant CP concentration of 10 ng L-1. Even at this low concentration, the alkylating agent caused modification of the life history parameters and proteome profile of the Daphnia. These changes were clone-specific and involved growth rate, age at first reproduction, neonate number, and proteins related to cell cycle and redox state regulation. The disturbance caused by pharmaceuticals contaminating freshwater ecosystem is probably weaker and unlikely to be cytotoxic in character due to the high dilution of these substances in the water. However, our results indicate that prolonged exposure of organisms to these toxins may lead to modifications on the organismal and molecular levels with unpredictable significance for the entire ecosystem
An Engineered Distant Homolog of Pseudomonas syringae TTSS Effector From Physcomitrella patens Can Act as a Bacterial Virulence Factor
Get PDFPseudomonas syringae pv. phaseolicola is the causative agent of halo blight in common bean (Phaseolus vulgaris). Similar to other pathogenic gram-negative bacteria, it secrets a set of type III effectors into host cells to subvert defense mechanisms. HopQ1 (for Hrp outer protein Q) is one of these type III effectors contributing to virulence of bacteria. Upon delivery into a plant cell, HopQ1 undergoes phosphorylation, binds host 14-3-3 proteins and suppresses defense-related signaling. Some plants however, evolved systems to recognize HopQ1 and respond to its presence and thus to prevent infection. HopQ1 shows homology to Nucleoside Hydrolases (NHs), but it contains a modified calcium binding motif not found in the canonical enzymes. CLuster ANalysis of Sequences (CLANS) revealed that HopQ1 and alike proteins make a distinct group of putative NHs located distantly from the classical enzymes. The HopQ1 – like protein (HLP) group comprises sequences from plant pathogenic bacteria, fungi, and lower plants. Our data suggest that the evolution of HopQ1 homologs in bacteria, fungi, and algae was independent. The location of moss HopQ1 homologs inside the fungal clade indicates a possibility of horizontal gene transfer (HGT) between those taxa. We identified a HLP in the moss Physcomitrella patens. Our experiments show that this protein (referred to as PpHLP) extended by a TTSS signal of HopQ1 promoted P. syringae growth in bean and was recognized by Nicotiana benthamiana immune system. Thus, despite the low sequence similarity to HopQ1 the engineered PpHLP acted as a bacterial virulence factor and displayed similar to HopQ1 virulence properties
Trichocera maculipennis (Diptera)—an invasive species in Maritime Antarctica
Get PDFAntarctica, with its severe conditions, is poor in terrestrial fauna species. However, an increase in human presence together with climate change may cause an influx of non-native species. Here we report a significant increase in colonized area of one of the few known invasive species to date in Antarctica. Non-native flies of Trichocera maculipennis have been recently observed in the Admiralty Bay area on King George Island, South Shetlands Islands, West Antarctica, 10 years after its first record in Maritime Antarctica (Maxwell Bay, King George Island). Its rapid spread across the island, despite geographic barriers such as glaciers, indicates successful adaptation to local environmental conditions and suggests this species is invasive. The mode of life of T. maculipennis, observed in natural and anthropogenous habitat and in laboratory conditions, is reported. The following adaptations enabled its invasion and existence within the sewage system in Antarctic scientific stations: the ability to survive in complete darkness, male ability to mate on the substrate surface without prior swarming in flight, and adaptation of terrestrial larvae to survive in semi-liquid food. Possible routes of introduction to Antarctica and between two bays on King George Island are discussed, as well as further research leading to the containment and eradication of this species