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PMID:21866103

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Citation

Carette, JE, Raaben, M, Wong, AC, Herbert, AS, Obernosterer, G, Mulherkar, N, Kuehne, AI, Kranzusch, PJ, Griffin, AM, Ruthel, G, Dal Cin, P, Dye, JM, Whelan, SP, Chandran, K and Brummelkamp, TR (2011) Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature 477:340-3

Abstract

Infections by the Ebola and Marburg filoviruses cause a rapidly fatal haemorrhagic fever in humans for which no approved antivirals are available. Filovirus entry is mediated by the viral spike glycoprotein (GP), which attaches viral particles to the cell surface, delivers them to endosomes and catalyses fusion between viral and endosomal membranes. Additional host factors in the endosomal compartment are probably required for viral membrane fusion; however, despite considerable efforts, these critical host factors have defied molecular identification. Here we describe a genome-wide haploid genetic screen in human cells to identify host factors required for Ebola virus entry. Our screen uncovered 67 mutations disrupting all six members of the homotypic fusion and vacuole protein-sorting (HOPS) multisubunit tethering complex, which is involved in the fusion of endosomes to lysosomes, and 39 independent mutations that disrupt the endo/lysosomal cholesterol transporter protein Niemann-Pick C1 (NPC1). Cells defective for the HOPS complex or NPC1 function, including primary fibroblasts derived from human Niemann-Pick type C1 disease patients, are resistant to infection by Ebola virus and Marburg virus, but remain fully susceptible to a suite of unrelated viruses. We show that membrane fusion mediated by filovirus glycoproteins and viral escape from the vesicular compartment require the NPC1 protein, independent of its known function in cholesterol transport. Our findings uncover unique features of the entry pathway used by filoviruses and indicate potential antiviral strategies to combat these deadly agents.

Links

PubMed PMC3175325 Online version:10.1038/nature10348

Keywords

Animals; Biological Transport; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell Line; Cholesterol/metabolism; Ebolavirus/physiology; Endosomes/metabolism; Fibroblasts/metabolism; Fibroblasts/pathology; Fibroblasts/virology; Genome, Human/genetics; Glycoproteins/metabolism; Haploidy; Hemorrhagic Fever, Ebola/drug therapy; Hemorrhagic Fever, Ebola/metabolism; Host-Pathogen Interactions/genetics; Humans; Lysosomes/metabolism; Marburg Virus Disease/drug therapy; Marburg Virus Disease/metabolism; Marburgvirus/physiology; Membrane Fusion/genetics; Membrane Fusion/physiology; Membrane Glycoproteins/deficiency; Membrane Glycoproteins/genetics; Membrane Glycoproteins/metabolism; Multiprotein Complexes/chemistry; Multiprotein Complexes/deficiency; Multiprotein Complexes/genetics; Multiprotein Complexes/metabolism; Mutation/genetics; Niemann-Pick Diseases/pathology; Niemann-Pick Diseases/virology; Receptors, Virus/metabolism; Viral Fusion Proteins/metabolism; Virus Internalization

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NPC1

involved_in

GO:0046718: viral entry into host cell

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NPC1

GO:0046718: entry of virus into host cell

ECO:0000315:

P

Fig. 4D

complete
CACAO 1966

MOUSE:NPC1

involved_in

GO:0046718: viral entry into host cell

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NPC1

GO:0046718: entry of virus into host cell

ECO:0000315:

P

Fig. 4

complete
CACAO 1967


See also

References

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