dictyNews
Electronic Edition
Volume 44, number 23
August 10, 2018
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Abstracts
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Cln3 function is linked to osmoregulation in a Dictyostelium model of
Batten disease
Sabateeshan Mathavarajah, Meagan McLaren, Robert J. Huber
Department of Biology, Trent University, Peterborough, Ontario, Canada
BBA Molecular Basis of Disease, in press
Mutations in CLN3 cause a juvenile form of neuronal ceroid lipofuscinosis
(NCL), commonly known as Batten disease. Currently, there is no cure for
NCL and the mechanisms underlying the disease are not well understood.
In the social amoeba Dictyostelium discoideum, the CLN3 homolog, Cln3,
localizes predominantly to the contractile vacuole (CV) system. This
dynamic organelle functions in osmoregulation, and intriguingly,
osmoregulatory defects have been observed in mammalian cell models of
CLN3 disease. Therefore, we used Dictyostelium to further study the
involvement of CLN3 in this conserved cellular process. First, we assessed
the localization of GFP-Cln3 during mitosis and cytokinesis, where CV
system function is essential. GFP-Cln3 localized to the CV system during
mitosis and cln3- cells displayed defects in cytokinesis. The recovery of
cln3- cells from hypotonic stress and their progression through multicellular
development was delayed and these effects were exaggerated when cells
were treated with ammonium chloride. In addition, Cln3-deficiency reduced
the viability of cells during hypotonic stress and impaired the integrity of
spores. During hypertonic stress, Cln3-deficiency reduced cell viability and
inhibited development. We then performed RNA sequencing to gain insight
into the molecular pathways underlying the sensitivity of cln3- cells to osmotic
stress. This analysis revealed that cln3-deficiency upregulated the expression
of tpp1A, the Dictyostelium homolog of human TPP1/CLN2. We used this
information to show a correlated increase in Tpp1 enzymatic activity in cln3-
cells. In total, our study provides new insight in the mechanisms underlying
the role of CLN3 in osmoregulation and neurodegeneration.
submitted by: Robert Huber [[log in to unmask]]
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The origins and evolution of macropinocytosis
Jason S. King1 and Rob R. Kay2
1 Department of Biomedical Sciences,University of Sheffield
2 MRC Laboratory of Molecular Biology, Cambridge
Philosophical Transactions of the Royal Society B, in press
In macropinocytosis, cells take up micron-sized droplets of medium into
internal vesicles. These vesicles are acidified and fused to lysosomes, their
contents digested and useful compounds extracted. Indigestible contents
can be exocytosed. Macropinocytosis has been known for approaching 100
years and is described in both metazoa and amoebae, but not in plants or
fungi. Its evolutionary origin goes back to at least the common ancestor of
the amoebozoa and opisthokonts, with apparent secondary loss from fungi.
The primary function of macropinocytosis in amoebae and some cancer cells
is feeding, but the conserved processing pathway for macropinosomes, which
involves shrinkage and the retrieval of membrane to the cell surface, has been
adapted in immune cells for antigen presentation. Macropinocytic cups are
large actin-driven processes, closely related to phagocytic cups and
pseudopods and appear to be organized around a conserved signalling patch
of PIP3, active Ras and active Rac that directs actin polymerization to its
periphery. Patches can form spontaneously and must be sustained by excitable
kinetics with strong cooperation from the actin cytoskeleton. Growth-factor
signalling shares core components with macropinocytosis, based around
phosphatidylinositol 3-kinase (PI3-kinase), and we suggest that it evolved to
take control of ancient feeding structures through a coupled growth factor
receptor.
submitted by: Jason King [[log in to unmask]]
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