Ebola virus entry requires the cholesterol transporter Niemann-Pick C1
By J. Carette, M. Raaben, A. Wong, A. Herbert, G. Obernosterer, Nirupama Mulherkar, A. Kuehne, P. Kranzusch, A. Griffin, G. Ruthel and 5 more. Nature, 2011
1,306 citations recorded by the source corpus.
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.
Subfields: Infectious Diseases, Public Health, Environmental and Occupational Health
View Paper: https://www.semanticscholar.org/paper/0b12e9bc230a0ff384198938e7f3b9382d0c99fb
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Citations in the corpus
- Viral membrane fusion (2015, background): “Although the initial cleavage occurs in the producing cell, generating a trimer of disulfide-linked GP(1):GP(2) subunits[46], fusion activation requires cathepsin-mediated cleavage after uptake into the new host cell, stripping GP(1) of much of its mass[47], and subsequent interaction with a specifi”
- RACK1 on and off the ribosome (2019, methodology): “As indicated, wild-type and DRACK1 (clone E3-A5) HAP1 cells were used in our studies (Carette et al. 2011; Jha et al. 2017).”