Sterol transfer by atypical cholesterol-binding NPC2 proteins in coral-algal symbiosis.
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ABSTRACT:
SUBMITTER: Hambleton EA
PROVIDER: S-EPMC6548501 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Niemann--Pick C disease is an inherited disorder in which cholesterol and other lipids accumulate in the late endosomal/lysosomal compartment. Recently, cyclodextrins (CD) have been shown to reduce symptoms and extend lifespan in animal models of the disease. In the present studies we examined the mechanism of sterol transport by CD using in vitro model systems and fluorescence spectroscopy and NPC2-deficient fibroblasts. We demonstrate that cholesterol transport from the lysosomal cholesterol-binding protein NPC2 to CD occurs via aqueous diffusional transfer and is very slow; the rate-limiting step appears to be dissociation of cholesterol from NPC2, suggesting that specific interactions between NPC2 and CD do not occur. In contrast, the transfer rate of the fluorescent cholesterol analogue dehydroergosterol (DHE) from CD to phospholipid membranes is very rapid and is directly proportional to the acceptor membrane concentration, as is DHE transfer from membranes to CD. Moreover, CD dramatically increases the rate of sterol transfer between membranes, with rates that can approach those mediated by NPC2. The results suggest that sterol transfer from CD to membranes occurs by a collisional transfer mechanism involving direct interaction of CD with membranes, similar to that shown previously for NPC2. For CD, however, absolute rates are slower compared to NPC2 for a given concentration, and the lysosomal phospholipid lysobisphosphatidic acid (LBPA) does not stimulate rates of sterol transfer between membranes and CD. As expected from the apparent absence of interaction between CD and NPC2, the addition of CD to NPC2-deficient fibroblasts rapidly rescued the cholesterol accumulation phenotype. Thus, the recent observations of CD efficacy in mouse models of NPC disease are likely the result of CD enhancement of cholesterol transport between membranes, with rapid sterol transfer occurring during CD--membrane interactions.
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Project description:Background: The molecular machinery underpinning the establishment of this relationship is not well understood. This is especially true of the symbiont side, as previous attempts to understand the interaction between coral larvae and Symbiodiniaceae have focused nearly exclusively on the host Results: In the current study, we utilised dual RNA-seq approach to study both symbiont and coral transcriptomes during symbiosis establishment. The transcriptomic response of C. goreaui to the symbiotic state was complex, the most obvious feature of which was extensive and generalized downregulation of gene expression. Included in this “symbiosis-derived transcriptional repression” were a range of stress response and immune-related genes. In contrast, a range of genes implicated in metabolism were upregulated in the symbiotic state. Consistent with previous ecological studies, this transcriptomic response of C. goreaui suggests that active translocation of metabolites to the host may begin early in the colonization process, and thus that the mutualistic relationship is established at the larval stage. The coral data imply the involvement of some SCRiP family members in the colonisation process and support the hypothesis that immune-suppression and arrest of phagosome maturation play important roles during the establishment of compatible symbioses. Conclusions: This study provides novel insights into the transcriptomic remodelling that occurs in C. goreaui during transition to a symbiotic lifestyle, with important implications for understanding the establishment of symbiosis between corals and their dinoflagellate partners.
2020-08-13 | GSE145030 | GEO
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Project description:The Niemann Pick type C (NPC) proteins, NPC1 and NPC2, are involved in the lysosomal storage disease, NPC disease. The formation of a NPC1?NPC2 protein?protein complex is believed to be necessary for the transfer of cholesterol and lipids out of the late endosomal (LE)/lysosomal (Lys) compartments. Mutations in either NPC1 or NPC2 can lead to an accumulation of cholesterol and lipids in the LE/Lys, the primary phenotype of the NPC disease. We investigated the NPC1(NTD)?NPC2 protein?protein complex computationally using two putative binding interfaces. A combination of molecular modeling and molecular dynamics simulations reveals atomic details that are responsible for interface stability. Cholesterol binding energies associated with each of the binding pockets for the two models are calculated. Analyses of the cholesterol binding in the two models support bidirectional ligand transfer when a particular interface is established. Based on the results, we propose that, depending on the location of the cholesterol ligand, a dynamical interface between the NPC2 and NPC1(NTD) proteins exists. Structural features of a particular interface can lower the energy barrier and stabilize the passage of the cholesterol substrate from NPC2 to NPC1(NTD).
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Project description:Background: The molecular machinery underpinning the establishment of this relationship is not well understood. This is especially true of the symbiont side, as previous attempts to understand the interaction between coral larvae and Symbiodiniaceae have focused nearly exclusively on the host Results: The transcriptomic response of C. goreaui to the symbiotic state was complex, the most obvious feature of which was extensive and generalized downregulation of gene expression. Included in this “symbiosis-derived transcriptional repression” were a range of stress response and immune-related genes. In contrast, a range of genes implicated in metabolism were upregulated in the symbiotic state. Consistent with previous ecological studies, this transcriptomic response of C. goreaui suggests that active translocation of metabolites to the host may begin early in the colonization process, and thus that the mutualistic relationship is established at the larval stage Conclusions: This study provides novel insights into the transcriptomic remodelling that occurs in C. goreaui during transition to a symbiotic lifestyle, with important implications for understanding the establishment of symbiosis between corals and their dinoflagellate partners.
2020-05-31 | GSE143202 | GEO