NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress

Höglinger, Doris; Burgoyne, Thomas; Sánchez-Heras, Elena; Hartwig, Pia; Colaço, Alexandria; Newton, Jason; Futter, Clare E.; Spiegel, Sarah; Platt, Frances M.; Eden, Emily R.

doi:10.1038/s41467-019-12152-2

Cited by 210 publications

(264 citation statements)

References 54 publications

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“…Additionally, NPC1 (Niemann-Pick intracellular cholesterol transporter 1), which facilitates export of cholesterol from the endolysosomal compartment, ranked highly in the 229E screen ( Fig. 1c) 30 . Overall, our data indicates a strong link between intracellular cholesterol levels and infection by all three coronavirus.…”

Section: Crispr Knockout Screens Identify Common and Virus-specific Cmentioning

confidence: 99%

Functional genomic screens identify human host factors for SARS-CoV-2 and common cold coronaviruses

Wang

Simoneau

Kulsuptrakul

et al. 2020

Preprint

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The Coronaviridae are a family of viruses that causes disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome. Finding host factors that are common to multiple coronaviruses could facilitate the development of therapies to combat current and future coronavirus pandemics. Here, we conducted parallel genome-wide CRISPR screens in cells infected by SARS-CoV-2 as well as two seasonally circulating common cold coronaviruses, OC43 and 229E. This approach correctly identified the distinct viral entry factors ACE2 (for SARS-CoV-2), aminopeptidase N (for 229E) and glycosaminoglycans (for OC43). Additionally, we discovered phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis as critical host pathways supporting infection by all three coronaviruses. By contrast, the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. Pharmacological inhibition of phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis reduced replication of all three coronaviruses. These findings offer important insights for the understanding of the coronavirus life cycle as well as the potential development of host-directed therapies.

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Section: Crispr Knockout Screens Identify Common and Virus-specific Cmentioning

confidence: 99%

Functional genomic screens identify human host factors for SARS-CoV-2 and common cold coronaviruses

Wang

Simoneau

Kulsuptrakul

et al. 2020

Preprint

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“…87 Subsequently, free cholesterol is effluxed out of the acidic organelle through a lysosomelocalized transmembrane cholesterol transporter, Niemann-Pick C1 (NPC1). [88][89][90][91] Subsequently, cholesterol is distributed heterogeneously to distinct membranes depending on their individual requirements. 92,93 Cholesterol can also be synthesized de novo in the endoplasmic reticulum (ER) by the coordinated actions of transcription factor sterol regulatory element-binding protein 2 (SREBP2), adapter proteins, and proteases.…”

Section: Nlrp3 Infl Amma Some Is Reg Ul Ated By Np C1 and Endopl A mentioning

confidence: 99%

Lipids, inflammasomes, metabolism, and disease

Anand

2020

Immunological Reviews

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Inflammasomes are multi‐protein complexes that regulate the cleavage of cysteine protease caspase‐1, secretion of inflammatory cytokines, and induction of inflammatory cell death, pyroptosis. Several members of the nod‐like receptor family assemble inflammasome in response to specific ligands. An exception to this is the NLRP3 inflammasome which is activated by structurally diverse entities. Recent studies have suggested that NLRP3 might be a sensor of cellular homeostasis, and any perturbation in distinct metabolic pathways results in the activation of this inflammasome. Lipid metabolism is exceedingly important in maintaining cellular homeostasis, and it is recognized that cells and tissues undergo extensive lipid remodeling during activation and disease. Some lipids are involved in instigating chronic inflammatory diseases, and new studies have highlighted critical upstream roles for lipids, particularly cholesterol, in regulating inflammasome activation implying key functions for inflammasomes in diseases with defective lipid metabolism. The focus of this review is to highlight how lipids regulate inflammasome activation and how this leads to the progression of inflammatory diseases. The key roles of cholesterol metabolism in the activation of inflammasomes have been comprehensively discussed. Besides, the roles of oxysterols, fatty acids, phospholipids, and lipid second messengers are also summarized in the context of inflammasomes. The overriding theme is that lipid metabolism has numerous but complex functions in inflammasome activation. A detailed understanding of this area will help us develop therapeutic interventions for diseases where dysregulated lipid metabolism is the underlying cause.

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“…Fourth, our results provide evidence supporting the role of cholesterol redistribution between the vesicle and PM in the regulation of the exocytotic fusion pore, as disease-related increases in vesicle cholesterol affected the fusion pore (Figure 7F) in a manner consistent with predictions by the model (Figure 5D). In Niemann-Pick disease type C1 mutations in NPC1, a protein involved in lysosome: ER contact site formation and therefore indirectly facilitating sterol transport (Hoglinger et al, 2019; Winkler et al, 2019), lead to an accumulation of vesicle cholesterol (Liscum, 2000; Mukherjee and Maxfield, 2004). In Npc1 − / − fibroblasts vesicles contained on average ∼2-fold more cholesterol (Figure 7A-D).…”

Section: Discussionmentioning

confidence: 99%

Redistribution of cholesterol from vesicle to plasmalemma controls fusion pore geometry

Rituper

Guček

Lisjak

et al. 2020

Preprint

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Highlights 36  Intravesicular cholesterol redistributes to the outer leaflet of the plasmalemma. 37 3  Cholesterol depletion widens the fusion pore, whereas cholesterol enrichment constricts the fusion 38 pore. 39  A model of cholesterol-dependent force preventing fusion pore widening is developed. 40  Disease-related increase in vesicle cholesterol constricts the fusion pore. 41 ABSTRACT 42 Eukaryotic vesicles fuse with the plasmalemma to form the fusion pore, previously considered to be 43 unstable with widening of the pore diameter. Recent studies established that the pore diameter is 44 stable, reflecting balanced forces of widening and closure. Proteins are considered key regulators of 45 the fusion pore, whereas the role of membrane lipids remains unclear. Super-resolution microscopy 46 revealed that lactotroph secretory vesicles discharge cholesterol after stimulation of exocytosis; 47 subsequently, vesicle cholesterol redistributes to the outer leaflet of the plasmalemma. Cholesterol 48 depletion in lactotrophs and astrocytes evokes release of vesicle hormone, indicating that cholesterol 49 constricts the fusion pore. A new model of cholesterol-dependent fusion pore diameter regulation is 50 proposed. High-resolution measurements of fusion pore conductance confirmed that the fusion pore 51 widens with cholesterol depletion and constricts with cholesterol enrichment. In fibroblasts lacking 52 the Npc1 protein, in which cholesterol accumulates in vesicles, the fusion pore is narrower than in 53 controls, showing that cholesterol regulates fusion pore geometry. 54 65 to the membrane area, and is affected by vesicle fusion and fission (Neher and Marty, 1982).66

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NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress

Cited by 210 publications

References 54 publications

Functional genomic screens identify human host factors for SARS-CoV-2 and common cold coronaviruses

Functional genomic screens identify human host factors for SARS-CoV-2 and common cold coronaviruses

Lipids, inflammasomes, metabolism, and disease

Redistribution of cholesterol from vesicle to plasmalemma controls fusion pore geometry

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