Methyl-CpG-binding (SmMBD2/3) and chromobox (SmCBX) proteins are required for neoblast proliferation and oviposition in the parasitic blood fluke Schistosoma mansoni

Autor: Narcis Fernandez-Fuentes, Dylan Phillips, Helen Whiteland, Karl F. Hoffmann, Kathrin K. Geyer, Sabrina E. Munshi
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Male
Schistosoma Mansoni
Somatic cell
Cellular differentiation
Oviposition
Polycomb-Group Proteins
Biochemistry
Epigenesis
Genetic
Mice
Small interfering RNAs
Biology (General)
DNA methylation
Eukaryota
Cell Differentiation
Helminth Proteins
Chromatin
3. Good health
Cell biology
Nucleic acids
DNA-Binding Proteins
Schistosoma
Epigenetics
Female
Schistosoma mansoni
Stem cell
DNA modification
Chromatin modification
Adult stem cell
Research Article
Chromosome biology
Signal Transduction
QH301-705.5
Immunology
Library Screening
Biology
Research and Analysis Methods
Microbiology
Host-Parasite Interactions
03 medical and health sciences
Protein Domains
Virology
Helminths
Genetics
Animals
Non-coding RNA
Molecular Biology Techniques
Molecular Biology
Methyl-CpG binding
Cell Proliferation
Molecular Biology Assays and Analysis Techniques
Life Cycle Stages
Organisms
Biology and Life Sciences
Proteins
DNA
RC581-607
biology.organism_classification
Invertebrates
Schistosomiasis mansoni
Gene regulation
030104 developmental biology
RNA
Parasitology
CpG Islands
Gene expression
Immunologic diseases. Allergy
Zdroj: PLoS Pathogens
PLoS Pathogens, Vol 14, Iss 6, p e1007107 (2018)
ISSN: 1553-7374
1553-7366
Popis: While schistosomiasis remains a significant health problem in low to middle income countries, it also represents a recently recognised threat to more economically-developed regions. Until a vaccine is developed, this neglected infectious disease is primarily controlled by praziquantel, a drug with a currently unknown mechanism of action. By further elucidating how Schistosoma molecular components cooperate to regulate parasite developmental processes, next generation targets will be identified. Here, we continue our studies on schistosome epigenetic participants and characterise the function of a DNA methylation reader, the Schistosoma mansoni methyl-CpG-binding domain protein (SmMBD2/3). Firstly, we demonstrate that SmMBD2/3 contains amino acid features essential for 5-methyl cytosine (5mC) binding and illustrate that adult schistosome nuclear extracts (females > males) contain this activity. We subsequently show that SmMBD2/3 translocates into nuclear compartments of transfected murine NIH-3T3 fibroblasts and recombinant SmMBD2/3 exhibits 5mC binding activity. Secondly, using a yeast-two hybrid (Y2H) screen, we show that SmMBD2/3 interacts with the chromo shadow domain (CSD) of an epigenetic adaptor, S. mansoni chromobox protein (SmCBX). Moreover, fluorescent in situ hybridisation (FISH) mediated co-localisation of Smmbd2/3 and Smcbx to mesenchymal cells as well as somatic- and reproductive- stem cells confirms the Y2H results and demonstrates that these interacting partners are ubiquitously expressed and found within both differentiated as well as proliferating cells. Finally, using RNA interference, we reveal that depletion of Smmbd2/3 or Smcbx in adult females leads to significant reductions (46–58%) in the number of proliferating somatic stem cells (PSCs or neoblasts) as well as in the quantity of in vitro laid eggs. Collectively, these results further expand upon the schistosome components involved in epigenetic processes and suggest that pharmacological inhibition of SmMBD2/3 and/or SmCBX biology could prove useful in the development of future schistosomiasis control strategies.
Author summary Schistosomiasis, caused by infection with blood fluke worms, is responsible for chronic disability and debilitating pathology in millions of infected individuals living in deprived regions of the developing world. Currently, schistosomiasis is primarily controlled by administration of a single drug (praziquantel) with a currently unknown mechanism of action and an inability to prevent reinfection or kill juvenile blood flukes. Therefore, to limit the spread and lower the global prevalence of this neglected infectious disease, praziquantel replacement or alternative strategies are urgently needed. One such strategy is to identify molecular targets essential for schistosome biology and to characterise how their loss of function affects parasite developmental processes. By doing so, new drug targets or vaccine candidates can be progressed. Here, we extend our work on the characterisation of Schistosoma mansoni epigenetic processes and reveal that two interacting components (S. mansoni methyl-CpG-binding domain protein, SmMBD2/3 and S. mansoni chromobox protein, SmCBX) are instrumental for maintaining the proliferative capacity of the single most important parasite cell population—proliferating schistosome stem cells (or neoblasts). We additionally demonstrate that these two proteins are necessary for maintaining schistosome egg production, a lifecycle feature responsible for human pathology and disease transmission. Developing drugs that disrupt the interaction of these epigenetic participants or inhibit their activity could highlight a novel approach for controlling schistosomiasis.
Databáze: OpenAIRE
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