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International Journal of Molecular... Feb 2020is gaining increasing attention as a model organism for the study of calcium binding and calmodulin function in basic biological events as well as human diseases. After... (Review)
Review
is gaining increasing attention as a model organism for the study of calcium binding and calmodulin function in basic biological events as well as human diseases. After a short overview of calcium-binding proteins, the structure of Dictyostelium calmodulin and the conformational changes effected by calcium ion binding to its four EF hands are compared to its human counterpart, emphasizing the highly conserved nature of this central regulatory protein. The calcium-dependent and -independent motifs involved in calmodulin binding to target proteins are discussed with examples of the diversity of calmodulin binding proteins that have been studied in this amoebozoan. The methods used to identify and characterize calmodulin binding proteins is covered followed by the ways is currently being used as a system to study several neurodegenerative diseases and how it could serve as a model for studying calmodulinopathies such as those associated with specific types of heart arrythmia. Because of its rapid developmental cycles, its genetic tractability, and a richly endowed stock center, is in a position to become a leader in the field of calmodulin research.
Topics: Binding Sites; Calcium; Calcium Signaling; Calmodulin; Calmodulin-Binding Proteins; Dictyostelium; EF Hand Motifs; Humans; Models, Molecular; Protein Binding; Protozoan Infections; Protozoan Proteins
PubMed: 32054133
DOI: 10.3390/ijms21041210 -
The International Journal of... 2019The social amoeba Dictyostelium discoideum has been a preferred model organism during the last 50 years, particularly for the study of cell motility and chemotaxis,... (Review)
Review
The social amoeba Dictyostelium discoideum has been a preferred model organism during the last 50 years, particularly for the study of cell motility and chemotaxis, phagocytosis and macropinocytosis, intercellular adhesion, pattern formation, caspase-independent cell death and more recently autophagy and social evolution. Being a soil amoeba and professional phagocyte, thus exposed to a variety of potential pathogens, D. discoideum has also proven to be a powerful genetic and cellular model for investigating host-pathogen interactions and microbial infections. The finding that the Dictyostelium genome harbours several homologs of human genes responsible for a variety of diseases has stimulated their analysis, providing new insights into the mechanism of action of the encoded proteins and in some cases into the defect underlying the disease. Recent technological developments have covered the genetic gap between mammals and non-mammalian model organisms, challenging the modelling role of the latter. Is there a future for Dictyostelium discoideum as a model organism?
Topics: Animals; Cell Biology; Cell Movement; Chemotaxis; Dictyostelium; Genome; History, 20th Century; History, 21st Century; Humans; Models, Biological; Phagocytosis
PubMed: 31840772
DOI: 10.1387/ijdb.190128sb -
The International Journal of... 2019By protein quality control and degradation, the ubiquitin system drives many essential regulatory processes such as cell cycle and division, signalling, DNA replication... (Review)
Review
By protein quality control and degradation, the ubiquitin system drives many essential regulatory processes such as cell cycle and division, signalling, DNA replication and repair. Therefore, dysfunctions in the ubiquitin system lead to many human disease states. However, despite the immense progress made over the last couple of decades, it appears that the ubiquitin system is more complex and multi-faced than formerly expected. In addition to a rich repertoire of ubiquitin, ubiquitin conjugating and de-ubiquitylating enzymes, the social amoeba Dictyostelium discoideum genome encodes also for a wide array of ubiquitin binding domain-containing proteins, thus offering the possibility to explore the biology of the ubiquitin system from cell and molecular biology points of view. We here provide an overview on the current knowledge about the Ub-system components and we discuss how Dictyostelium might be an outstanding eukaryotic cell model for unravelling the still mostly unknown ubiquitination mechanisms of some human diseases.
Topics: Animals; Cell Biology; Dictyostelium; Humans; Mice; Models, Biological; Plasmids; Proteasome Endopeptidase Complex; Protein Binding; Protein Domains; Protein Processing, Post-Translational; Proteolysis; RNA Interference; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 31840790
DOI: 10.1387/ijdb.190260eb -
The International Journal of... 2019The social amoeba Dictyostelium discoideum is a tractable model organism to study cellular allorecognition, which is the ability of a cell to distinguish itself and its... (Review)
Review
The social amoeba Dictyostelium discoideum is a tractable model organism to study cellular allorecognition, which is the ability of a cell to distinguish itself and its genetically similar relatives from more distantly related organisms. Cellular allorecognition is ubiquitous across the tree of life and affects many biological processes. Depending on the biological context, these versatile systems operate both within and between individual organisms, and both promote and constrain functional heterogeneity. Some of the most notable allorecognition systems mediate neural self-avoidance in flies and adaptive immunity in vertebrates. D. discoideum's allorecognition system shares several structures and functions with other allorecognition systems. Structurally, its key regulators reside at a single genomic locus that encodes two highly polymorphic proteins, a transmembrane ligand called TgrC1 and its receptor TgrB1. These proteins exhibit isoform-specific, heterophilic binding across cells. Functionally, this interaction determines the extent to which co-developing D. discoideum strains co-aggregate or segregate during the aggregation phase of multicellular development. The allorecognition system thus affects both development and social evolution, as available evidence suggests that the threat of developmental cheating represents a primary selective force acting on it. Other significant characteristics that may inform the study of allorecognition in general include that D. discoideum's allorecognition system is a continuous and inclusive trait, it is pleiotropic, and it is temporally regulated.
Topics: Adaptive Immunity; Cell Adhesion; Chemotaxis; Dictyostelium; Glycoproteins; Glycosylation; Ligands; Models, Biological; Phenotype; Protozoan Proteins
PubMed: 31840777
DOI: 10.1387/ijdb.190239gs -
The International Journal of... 2019Multi-protein complexes mTORC1 and mTORC2 are required for growth and development of eukaryotes. mTORC1 is a nutrient sensor that integrates metabolic signals and energy... (Review)
Review
Multi-protein complexes mTORC1 and mTORC2 are required for growth and development of eukaryotes. mTORC1 is a nutrient sensor that integrates metabolic signals and energy state to regulate cell growth/proliferation, whereas, mTORC2 primarily regulates developmental processes. Dictyostelium proliferate in rich growth media, but initiate development upon nutrient depletion. Both mTOR complexes play essential roles in Dictyostelium, where growth and developmental cycles independently require, respectively, mTORC1 or mTORC2. Many protein associations and regulatory pathways for mTORC1 and mTORC2 in Dictyostelium have context similarity to mammalian cells and specificity to inhibition by the immunosuppressive drug rapamycin. In Dictyostelium, mTORC1 function is inactivated upon starvation-induced development, but development is directly induced through rapamycin-mediated inhibition of mTORC1 activity, even in the absence of nutrient withdrawal. Pharmacologic inhibition of mTORC1, in the absence of nutrient loss, has allowed the identification of a class of essential up-regulated, developmentally-associated signaling genes and down-regulated, growth genes. We also review functional pathway regulations that integrate mTORC1/mTORC2 activities and emphasize complexity of small GTPase regulation of mTORC2 activity. Finally, epistases experiments have suggested novel upstream pathway cross-talk in Dictyostelium that requires mTORC1 and mTORC2, but for separate and independent downstream functions.
Topics: Adenylyl Cyclases; Cell Proliferation; Dictyostelium; Down-Regulation; GTP Phosphohydrolases; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Signal Transduction; Sirolimus; Up-Regulation
PubMed: 31840789
DOI: 10.1387/ijdb.190245ak -
Genome Research Aug 2021development begins with single-cell starvation and ends with multicellular fruiting bodies. Developmental morphogenesis is accompanied by sweeping transcriptional...
development begins with single-cell starvation and ends with multicellular fruiting bodies. Developmental morphogenesis is accompanied by sweeping transcriptional changes, encompassing nearly half of the 13,000 genes in the genome. We performed time-series RNA-sequencing analyses of the wild type and 20 mutants to explore the relationships between transcription and morphogenesis. These strains show developmental arrest at different stages, accelerated development, or atypical morphologies. Considering eight major morphological transitions, we identified 1371 milestone genes whose expression changes sharply between consecutive transitions. We also identified 1099 genes as members of 21 regulons, which are groups of genes that remain coordinately regulated despite the genetic, temporal, and developmental perturbations. The gene annotations in these groups validate known transitions and reveal new developmental events. For example, DNA replication genes are tightly coregulated with cell division genes, so they are expressed in mid-development although chromosomal DNA is not replicated. Our data set includes 486 transcriptional profiles that can help identify new relationships between transcription and development and improve gene annotations. We show its utility by showing that cycles of aggregation and disaggregation in allorecognition-defective mutants involve dedifferentiation. We also show sensitivity to genetic and developmental conditions in two commonly used actin genes, and , and robustness of the gene. Finally, we propose that is a better mRNA quantitation standard because it is less sensitive to external conditions than commonly used standards. The data set is available for democratized exploration through the web application dictyExpress and the data mining environment Orange.
Topics: Dictyostelium; Morphogenesis; RNA, Messenger; Regulon; Software
PubMed: 34183452
DOI: 10.1101/gr.275496.121 -
International Journal of Molecular... Oct 2017Signal transduction through G-protein-coupled receptors (GPCRs) is central for the regulation of virtually all cellular functions, and it has been widely implicated in... (Review)
Review
Signal transduction through G-protein-coupled receptors (GPCRs) is central for the regulation of virtually all cellular functions, and it has been widely implicated in human diseases. These receptors activate a common molecular switch that is represented by the heterotrimeric G-protein generating a number of second messengers (cAMP, cGMP, DAG, IP3, Ca etc.), leading to a plethora of diverse cellular responses. Spatiotemporal regulation of signals generated by a given GPCR is crucial for proper signalling and is accomplished by a series of biochemical modifications. Over the past few years, it has become evident that many signalling proteins also undergo ubiquitination, a posttranslational modification that typically leads to protein degradation, but also mediates processes such as protein-protein interaction and protein subcellular localization. The social amoeba has proven to be an excellent model to investigate signal transduction triggered by GPCR activation, as cAMP signalling via GPCR is a major regulator of chemotaxis, cell differentiation, and multicellular morphogenesis. Ubiquitin ligases have been recently involved in these processes. In the present review, we will summarize the most significant pathways activated upon GPCRs stimulation and discuss the role played by ubiquitination in cells.
Topics: Dictyostelium; Protozoan Proteins; Receptors, G-Protein-Coupled; Signal Transduction; Ubiquitination
PubMed: 29048338
DOI: 10.3390/ijms18102180 -
The International Journal of... 2019Macropinocytosis is used by a variety of amoebae for feeding on liquid medium. The amoebae project cups and ruffles from their plasma membrane, driven by actin... (Review)
Review
Macropinocytosis is used by a variety of amoebae for feeding on liquid medium. The amoebae project cups and ruffles from their plasma membrane, driven by actin polymerization, and eventually fuse these back to the membrane, entrapping droplets of medium into internal vesicles. These vesicles are of up to several microns in diameter and are processed through the lysosomal digestive system to extract nutrients. Recognizably the same process is used in metazoan cells for a number of medically important purposes, including the pathological growth of cancer cells. We describe the discovery of macropinocytosis in Dictyostelium amoebae, its genetic regulation by the NF1 RasGAP, and the tools available for its investigation. Work on Dictyostelium over the last 30 years has identified many genes that may be important for macropinocytosis, which are listed at dictyBase, and give a basis for mechanistic studies. We argue that the actin cytoskeleton is organized for macropinocytosis by a signalling patch of PIP3 and active Ras and Rac, together with their regulatory proteins and effectors, including the protein kinases Akt and SGK. The Scar/WAVE complex is recruited to the periphery of this patch, triggering the formation of a hollow ring of protrusive actin polymerization, and eventually a macropinocytic cup. Major problems to be addressed include: the dynamics sustaining macropinocytic patches and the mechanism of Scar/WAVE recruitment; the mechanisms of cup closure and of membrane fusion; the ecological situations where amoebae feed by macropinocytosis; and the evolutionary relationship between macropinocytosis and growth factor signalling.
Topics: Actin Cytoskeleton; Actins; Animals; Cell Membrane; Dictyostelium; Lysosomes; Microscopy; Phosphatidylinositol 3-Kinases; Pinocytosis; Signal Transduction; rac GTP-Binding Proteins; ras Proteins
PubMed: 31840785
DOI: 10.1387/ijdb.190220rk -
Developmental Biology Jun 2015Cells grow, move, expand, shrink and die in the process of generating the characteristic shapes of organisms. Although the structures generated during development of the... (Review)
Review
Cells grow, move, expand, shrink and die in the process of generating the characteristic shapes of organisms. Although the structures generated during development of the social amoeba Dictyostelium discoideum look nothing like the structures seen in metazoan embryogenesis, some of the morphogenetic processes used in their making are surprisingly similar. Recent advances in understanding the molecular basis for directed cell migration, cell type specific sorting, differential adhesion, secretion of matrix components, pattern formation, regulation and terminal differentiation are reviewed. Genes involved in Dictyostelium aggregation, slug formation, and culmination of fruiting bodies are discussed.
Topics: Cell Shape; Chemotaxis; Cyclic AMP; Dictyostelium; Extracellular Matrix; Gene Expression Regulation, Developmental; Models, Biological; Morphogenesis
PubMed: 25872182
DOI: 10.1016/j.ydbio.2015.03.016 -
Current Opinion in Biotechnology Oct 2022The identification of novel platform organisms for the production and discovery of small molecules is of high interest for the pharmaceutical industry. In particular,... (Review)
Review
The identification of novel platform organisms for the production and discovery of small molecules is of high interest for the pharmaceutical industry. In particular, the structural complexity of most natural products with therapeutic potential restricts an industrial production since chemical syntheses often require complex multistep routes. The amoeba Dictyostelium discoideum can be easily cultivated in bioreactors due to its planktonic growth behavior and contains numerous polyketide and terpene synthase genes with only a few compounds being already elucidated. Hence, the amoeba both bears a wealth of hidden natural products and allows for the development of new bioprocesses for existing pharmaceuticals. In this mini review, we present D. discoideum as a novel platform for the production of complex secondary metabolites and discuss its suitability for industrial processes. We also provide initial insights into future bioprocesses, both involving bacterial coculture setups and for the production of plant-based pharmaceuticals.
Topics: Amoeba; Bacteria; Biological Products; Dictyostelium; Pharmaceutical Preparations
PubMed: 35944344
DOI: 10.1016/j.copbio.2022.102766