Abstract
There are no approved therapies for Ebola virus infection. Here, to find potential therapeutic targets, we perform a screen for genes essential for Ebola virus (EBOV) infection. We identify GNPTAB, which encodes the α and β subunits of N-acetylglucosamine-1-phosphate transferase. We show that EBOV infection of a GNPTAB knockout cell line is impaired, and that this is reversed by reconstituting GNPTAB expression. Fibroblasts from patients with mucolipidosis II, a disorder associated with mutations in GNPTAB, are refractory to EBOV, whereas cells from their healthy parents support infection. Impaired infection correlates with loss of the expression of cathepsin B, known to be essential for EBOV entry. GNPTAB activity is dependent upon proteolytic cleavage by the SKI-1/S1P protease. Inhibiting this protease with the small-molecule PF-429242 blocks EBOV entry and infection. Disruption of GNPTAB function may represent a strategy for a host-targeted therapy for EBOV.
Highlights
There are no approved therapies for Ebola virus infection
Niemann-Pick C1 (NPC1) was the strongest hit in this screen, but other hits included genes from the homotypic fusion and vacuole protein sorting (HOPS) complex, which is involved in the fusion of endosomes to lysosomes; cathepsin B (CTSB)[15]; the lipid kinase PIKFYVE16; and N-acetylglucosamine-1-phosphate transferase alpha and beta subunits (GNPTAB)
We find that an inhibitor of the SKI-1/S1P protease required for GNPTAB activity blocks Ebola virus (EBOV) infection, suggesting that targeting GNPTAB may be a strategy for a host-targeted antiviral therapy for EBOV
Summary
There are no approved therapies for Ebola virus infection. Here, to find potential therapeutic targets, we perform a screen for genes essential for Ebola virus (EBOV) infection. NPC1 was the strongest hit in this screen, but other hits included genes from the homotypic fusion and vacuole protein sorting (HOPS) complex, which is involved in the fusion of endosomes to lysosomes; cathepsin B (CTSB)[15]; the lipid kinase PIKFYVE16; and N-acetylglucosamine-1-phosphate transferase alpha and beta subunits (GNPTAB). Another genome-wide screen used short-interfering RNA (siRNA) in A549 cells, using lentivirus bearing the MARV glycoprotein[17]. This screen identified carbamoyl-phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase (CAD) and the de novo pyrimidine synthesis pathway as being essential for EBOV replication and transcription
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
