Stress and development in <i>Dictyostelium discoideum</i>: the involvement of the catalytic calcineurin A subunit

Thewes, Sascha; Schubert, Sebastian K.; Park, Kyuhyeon; Mutzel, Rupert

doi:10.1002/jobm.201200574

Cited by 9 publications

(14 citation statements)

References 56 publications

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“…It has been shown in virulence assays that Crz1 has a moderate effect on virulence whereas calcineurin is essential in a mouse model of infection (22). However, this discrepancy in the phenotypical outcome of mutations of calcineurin and its downstream targets has also been observed frequently in other studies (5,14,31,70) and shows that calcineurin has other targets apart from Crz1. Crz1 is also involved in virulence in other Candida species.…”

Section: Calcineurin-crz1 Signaling and Virulencementioning

confidence: 94%

“…As stated above, in addition to the fungal kingdom, calcineurin has been investigated in other lower eukaryotes such as social amoebae (4,5), various parasites (6-8, 11), and amoeboflagellates (97) and in Paramecium (12).…”

Section: Calcineurin-crz1 Signaling Beyond the Fungal Kingdommentioning

confidence: 99%

“…However, in the last decade calcineurin has also been investigated more extensively in filamentous fungi (reviewed in reference 3) as well as in other lower eukaryotes such as the social amoeba Dictyostelium discoideum (4,5), the parasites Plasmodium falciparum (6), Trypanosoma cruzi (7,8), Trypanosoma rangeli (9), Schistosoma mansoni (10), and Leishmania major (11), and in Paramecium tetraurelia (12). Furthermore, many target proteins of this phosphatase have been identified in different organisms (reviewed in reference 13).…”

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confidence: 99%

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Calcineurin-Crz1 Signaling in Lower Eukaryotes

2014

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Calcium ions are ubiquitous intracellular messengers. An increase in the cytosolic Ca 2؉ concentration activates many proteins, including calmodulin and the Ca 2؉ /calmodulin-dependent protein phosphatase calcineurin. The phosphatase is conserved from yeast to humans (except in plants), and many target proteins of calcineurin have been identified. The most prominent and bestinvestigated targets, however, are the transcription factors NFAT (nuclear factor of activated T cells) in mammals and Crz1 (calcineurin-responsive zinc finger 1) in yeast. In recent years, many orthologues of Crz1 have been identified and characterized in various species of fungi, amoebae, and other lower eukaryotes. It has been shown that the functions of calcineurin-Crz1 signaling, ranging from ion homeostasis through cell wall biogenesis to the building of filamentous structures, are conserved in the different organisms. Furthermore, frequency-modulated gene expression through Crz1 has been discovered as a striking new mechanism by which cells can coordinate their response to a signal. In this review, I focus on the latest findings concerning calcineurin-Crz1 signaling in fungi, amoebae and other lower eukaryotes. I discuss the potential of Crz1 and its orthologues as putative drug targets, and I also discuss possible parallels with calcineurin-NFAT signaling in mammals.

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Section: Calcineurin-crz1 Signaling and Virulencementioning

confidence: 94%

Section: Calcineurin-crz1 Signaling Beyond the Fungal Kingdommentioning

confidence: 99%

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confidence: 99%

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Calcineurin-Crz1 Signaling in Lower Eukaryotes

2014

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“…Since CanA, the sole CaM‐dependent protein phosphatase, dephosphorylates both serine and threonine residues, it was suggested that it could function during folic acid‐mediated chemotaxis. CanA was the first CaMBP to be characterized in D. discoideum (Catalano & O'Day, ; Damman et al ., Dammann et al, ; Thewes et al, ). However, despite its role in a diversity of chemotactic events in other species, investigations into the role of CanA suggest it is not linked to folic acid‐mediated chemotaxis.…”

Section: Cell Motility and Chemotaxis During Growthmentioning

confidence: 99%

Calmodulin‐mediated events during the life cycle of the amoebozoan Dictyostelium discoideum

et al. 2019

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This review focusses on the functions of intracellular and extracellular calmodulin, its target proteins and their binding proteins during the asexual life cycle of Dictyostelium discoideum. Calmodulin is a primary regulatory protein of calcium signal transduction that functions throughout all stages. During growth, it mediates autophagy, the cell cycle, folic acid chemotaxis, phagocytosis, and other functions. During mitosis, specific calmodulin‐binding proteins translocate to alternative locations. Translocation of at least one cell adhesion protein is calmodulin dependent. When starved, cells undergo calmodulin‐dependent chemotaxis to cyclic AMP generating a multicellular pseudoplasmodium. Calmodulin‐dependent signalling within the slug sets up a defined pattern and polarity that sets the stage for the final events of morphogenesis and cell differentiation. Transected slugs undergo calmodulin‐dependent transdifferentiation to re‐establish the disrupted pattern and polarity. Calmodulin function is critical for stalk cell differentiation but also functions in spore formation, events that begin in the pseudoplasmodium. The asexual life cycle restarts with the calmodulin‐dependent germination of spores. Specific calmodulin‐binding proteins as well as some of their binding partners have been linked to each of these events. The functions of extracellular calmodulin during growth and development are also discussed. This overview brings to the forefront the central role of calmodulin, working through its numerous binding proteins, as a primary downstream regulator of the critical calcium signalling pathways that have been well established in this model eukaryote. This is the first time the function of calmodulin and its target proteins have been documented through the complete life cycle of any eukaryote.

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“…However, to the best of our knowledge, they do not appear to affect calcineurin, and thus, their precise mechanism of action remains to be elucidated. 39,40 A commonly used drug, FK506 (also known as tacrolimus), indirectly inhibits calcineurin activity by binding to a separate protein, FKBP, together forming a potent antagonist. 27 Interestingly, the Legionella protein Mip (macrophage infectivity potentiator) shares structural similarity to the FKBP protein family, and Mip proteins are also known to bind FK506.…”

Section: ■ Discussionmentioning

confidence: 99%

Amoebae-Based Screening Reveals a Novel Family of Compounds Restricting Intracellular Legionella pneumophila

et al. 2015

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The causative agent of Legionnaires' disease, Legionella pneumophila, grows in environmental amoebae and mammalian macrophages within a distinct compartment, the 'Legionella-containing vacuole' (LCV). Intracellular bacteria are protected from many antibiotics, and thus are notoriously difficult to eradicate. To identify novel compounds that restrict intracellular bacterial replication, we previously developed an assay based on a coculture of amoebae and GFP-producing L. pneumophila. This assay was used to screen a pathway-based, highly diverse chemical library, referred to as the Sinergia library. In this work, we chose to focus on a group of 11 hit compounds, the majority of which originated from the query molecule CN585, a compound that targets the protein phosphatase calcineurin. Further studies on 78 related compound variants revealed crucial structural attributes, namely a triple-ring scaffold with a central triazine moiety, substituted in positions 3 and 5 by two piperidine or pyrrolidine rings, and in position 1 by an amine group bearing a single aliphatic chain moiety. The most effective compound, ZINC00615682, inhibited intracellular replication of L. pneumophila with an IC50 of approximately 20 nM in Acanthamoeba castellanii and slightly less efficiently in Dictyostelium discoideum or macrophages. Pharmacological and genetic attempts to implicate calcineurin in the intracellular replication of L. pneumophila failed. Taken together, these results show that the amoebae-based screen and structure-activity relationship analysis is suitable for the identification of novel inhibitors of the intracellular replication of L. pneumophila. The most potent compound identified in this study targets (an) as yet unidentified host factor(s).

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Stress and development in Dictyostelium discoideum: the involvement of the catalytic calcineurin A subunit

Cited by 9 publications

References 56 publications

Calcineurin-Crz1 Signaling in Lower Eukaryotes

Calcineurin-Crz1 Signaling in Lower Eukaryotes

Calmodulin‐mediated events during the life cycle of the amoebozoan Dictyostelium discoideum

Amoebae-Based Screening Reveals a Novel Family of Compounds Restricting Intracellular Legionella pneumophila

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