Host PI(3,5)P2 activity is required for Plasmodium berghei growth during liver stage infection.
Ontology highlight
ABSTRACT:
SUBMITTER: Thieleke-Matos C
PROVIDER: S-EPMC4267720 | biostudies-literature | 2014 Oct
REPOSITORIES: biostudies-literature
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Project description:The intracellular lifestyle represents a challenge for the rapidly proliferating liver stage Plasmodium parasite. In order to scavenge host resources, Plasmodium has evolved the ability to target and manipulate host cell organelles. Using dynamic fluorescence-based imaging, we here show an interplay between the pre-erythrocytic stages of Plasmodium berghei and the host cell Golgi during liver stage development. Liver stage schizonts fragment the host cell Golgi into miniaturized stacks, which increases surface interactions with the parasitophorous vacuolar membrane of the parasite. Expression of specific dominant-negative Arf1 and Rab GTPases, which interfere with the host cell Golgi-linked vesicular machinery, results in developmental delay and diminished survival of liver stage parasites. Moreover, functional Rab11a is critical for the ability of the parasites to induce Golgi fragmentation. Altogether, we demonstrate that the structural integrity of the host cell Golgi and Golgi-associated vesicular traffic is important for optimal pre-erythrocytic development of P. berghei. The parasite hijacks the Golgi structure of the hepatocyte to optimize its own intracellular development. This article has an associated First Person interview with the first author of the paper.
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Project description:Lysosomes are dynamic organelles with critical roles in cellular physiology. The lysosomal signaling lipid phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) is a key regulator that has been implicated to control lysosome ion homeostasis, but the scope of ion transporters targeted by PI(3,5)P2 and the purpose of this regulation is not well understood. Through an unbiased screen in Saccharomyces cerevisiae, we identified loss-of-function mutations in the vacuolar H+-ATPase (V-ATPase) and in Vnx1, a vacuolar monovalent cation/proton antiporter, as suppressor mutations that relieve the growth defects and osmotic swelling of vacuoles (lysosomes) in yeast lacking PI(3,5)P2. We observed that depletion of PI(3,5)P2 synthesis in yeast causes a robust accumulation of multiple cations, most notably an ∼85 mM increase in the cellular concentration of potassium, a critical ion used by cells to regulate osmolarity. The accumulation of potassium and other cations in PI(3,5)P2-deficient yeast is relieved by mutations that inactivate Vnx1 or inactivate the V-ATPase and by mutations that increase the activity of a vacuolar cation export channel, Yvc1. Collectively, our data demonstrate that PI(3,5)P2 signaling orchestrates vacuole/lysosome cation transport to aid cellular osmoregulation.
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Project description:Dynamic regulation of phosphoinositide lipids (PIPs) is crucial for diverse cellular functions, and, in neurons, PIPs regulate membrane trafficking events that control synapse function. Neurons are particularly sensitive to the levels of the low abundant PIP, phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2], because mutations in PI(3,5)P2-related genes are implicated in multiple neurological disorders, including epilepsy, severe neuropathy, and neurodegeneration. Despite the importance of PI(3,5)P2 for neural function, surprisingly little is known about this signaling lipid in neurons, or any cell type. Notably, the mammalian homolog of yeast vacuole segregation mutant (Vac14), a scaffold for the PI(3,5)P2 synthesis complex, is concentrated at excitatory synapses, suggesting a potential role for PI(3,5)P2 in controlling synapse function and/or plasticity. PI(3,5)P2 is generated from phosphatidylinositol 3-phosphate (PI3P) by the lipid kinase PI3P 5-kinase (PIKfyve). Here, we present methods to measure and control PI(3,5)P2 synthesis in hippocampal neurons and show that changes in neural activity dynamically regulate the levels of multiple PIPs, with PI(3,5)P2 being among the most dynamic. The levels of PI(3,5)P2 in neurons increased during two distinct forms of synaptic depression, and inhibition of PIKfyve activity prevented or reversed induction of synaptic weakening. Moreover, altering neuronal PI(3,5)P2 levels was sufficient to regulate synaptic strength bidirectionally, with enhanced synaptic function accompanying loss of PI(3,5)P2 and reduced synaptic strength following increased PI(3,5)P2 levels. Finally, inhibiting PI(3,5)P2 synthesis alters endocytosis and recycling of AMPA-type glutamate receptors (AMPARs), implicating PI(3,5)P2 dynamics in AMPAR trafficking. Together, these data identify PI(3,5)P2-dependent signaling as a regulatory pathway that is critical for activity-dependent changes in synapse strength.
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