dictyNews
Electronic Edition
Volume 45, number 29
November 8, 2019
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Abstracts
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Kil2 activity and intracellular killing.
Bodinier R, Leiba J, Sabra A, Jauslin TN, Lamrabet O, Guilhen C,
Marchetti A, Iwade Y, Kawata T, Lima WC, Cosson P.
Cell Microbiol. 2019 Oct 25:e13129. doi: 10.1111/cmi.13129.
[Epub ahead of print]
Phagocytic cells ingest bacteria by phagocytosis and kill them efficiently
inside phagolysosomes. The molecular mechanisms involved in
intracellular killing and their regulation are complex and still incompletely
understood. Dictyostelium discoideum has been used as a model to
discover and to study new gene products involved in intracellular killing
of ingested bacteria. In this study, we performed random mutagenesis of
Dictyostelium cells, and isolated a mutant defective for growth on bacteria.
This mutant is characterized by the genetic inactivation of the lrrkA gene,
which encodes a protein with a kinase domain and leucine-rich repeats.
LrrkA knockout (KO) cells kill ingested K. pneumoniae bacteria inefficiently.
This defect is not additive to the killing defect observed in kil2 KO cells,
suggesting that the function of Kil2 is partially controlled by LrrkA. Indeed,
lrrkA KO cells exhibit a phenotype similar to that of kil2 KO cells:
intraphagosomal proteolysis is inefficient and both intraphagosomal killing
and proteolysis are restored upon exogenous supplementation with
magnesium ions. Bacterially secreted folate stimulates intracellular killing
in Dictyostelium cells, but this stimulation is lost in cells with genetic
inactivation of kil2, lrrkA or far1. Together these results indicate that the
stimulation of intracellular killing by folate involves Far1 (the cell surface
receptor for folate), LrrkA and Kil2. This study is the first identification of
a signaling pathway regulating intraphagosomal bacterial killing in
Dictyostelium cells.
submitted by: Pierre Cosson [[log in to unmask]]
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Dyskerin mutations present in Dyskeratosis congenita patients increase
oxidative stress and DNA damage signalling in Dictyostelium discoideum.
Javier Rodriguez-Centeno, Rosario Perona and Leandro Sastre
Cells, in press
Dyskerin is a protein involved in the formation of small nucleolar and
small Cajal body ribonucleoproteins. These complexes participate in RNA
pseudouridylation and are also components of the telomerase complex
required for telomere elongation. Dyskerin mutations cause a rare disease,
X-linked dyskeratosis congenita, with no curative treatment. The social
amoeba Dictyostelium discoideum contains a gene coding for a dyskerin
homologous protein. In this article D. discoideum mutant strains that have
mutations corresponding to mutations found in dyskeratosis congenita
patients are described. The phenotype of the mutant strains has been
studied and no alterations were observed in pseudouridylation activity and
telomere structure. Mutant strains showed increased proliferation on liquid
culture but reduced growth feeding on bacteria. The results obtained
indicated the existence of increased DNA damage response and reactive
oxygen species, as also reported in human Dyskeratosis congenita cells
and some other disease models. These data, together with the haploid
character of D. discoideum vegetative cells, that resemble the genomic
structure of the human dyskerin gene, located in the X chromosome,
support the conclusion that D. discoideum can be a good model system
for the study of this disease.
submitted by: Leandro Sastre [[log in to unmask]]
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A new mechanism for Cannabidiol in regulating the one-carbon cycle and
methionine levels in Dictyostelium and in mammalian epilepsy models
Christopher J Perry, Paul Finch, Annette Müller-Taubenberger, Kit-Yi
Leung, Eleanor Warren, Joseph Damstra-Oddy, Devdutt Sharma, Pabitra
H Patra, Sarah Glyn, Joanna Boberska, Balint Stewart, Amy Baldwin,
Fabiana Piscitelli, Robert J Harvey, Adrian Harwood, Christopher
Thompson, Sandrine Claus, Nicholas DE Greene, Alister McNeish,
Claire M Williams, Benjamin J Whalley, Robin SB Williams
British Journal of Pharmacology, doi 10.1111/bph.14892
Background and Purpose: Epidiolex, a form of highly purified cannabidiol
(CBD) derived from Cannabis plants has demonstrated seizure control
activity in patients with Dravet syndrome, without a fully elucidated
mechanism of action. We have employed an unbiased approach to
investigate this mechanism at a cellular level.
Experimental Approach: We use a tractable biomedical model organism,
Dictyostelium, to identify protein controlling the effect of CBD and
characterize this mechanism. We then translate these results to a
Dravet Syndrome mouse model and an acute in vitro seizure model.
Key Results: CBD activity is partially dependent upon the mitochondrial
glycine cleavage system component, GcvH1 in Dictyostelium,
orthologous to the human GCSH protein, which is functionally linked to
folate one-carbon metabolism (FOCM). Analysis of FOCM components
identified a mechanism for CBD in directly inhibiting methionine synthesis.
Analysis of brain tissue from a Dravet syndrome mouse model also
showed drastically altered levels of one-carbon components including
methionine, and an in vitro rat seizure model showed an elevated level
of methionine that is attenuated following CBD treatment.
Conclusions and Implications: Our results suggest a novel mechanism
for CBD in the regulating methionine levels, and identify altered one-
carbon metabolism in Dravet syndrome and seizure activity.
submitted by: Robin Williams [[log in to unmask]]
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[End dictyNews, volume 45, number 29]
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