| Title: |
Class III Phosphatidylinositol 4-Kinase Alpha and Beta Are Novel Host Factor Regulators of Hepatitis C Virus Replication |
| Authors: |
Borawski, Jason; Troke, Philip; Puyang, Xiaoling; Gibaja, Veronica; Zhao, ShanChaun; Mickanin, Craig; Leighton-Davies, Juliet; Wilson, Christopher J.; Myer, Vic; CornellaTaracido, Ivan; Baryza, Jeremy; Tallarico, John; Joberty, Gerard; Bantscheff, Marcus; Schirle, Markus; Bouwmeester, Tewis; Mathy, Joanna E.; Lin, Kai; Compton, Teresa; Labow, Mark; Wiedmann, Brigitte; Gaither, L. Alex |
| Source: |
Journal of Virology ; volume 83, issue 19, page 10058-10074 ; ISSN 0022-538X 1098-5514 |
| Publisher Information: |
American Society for Microbiology |
| Publication Year: |
2009 |
| Description: |
Host factor pathways are known to be essential for hepatitis C virus (HCV) infection and replication in human liver cells. To search for novel host factor proteins required for HCV replication, we screened a subgenomic genotype 1b replicon cell line (Luc-1b) with a kinome and druggable collection of 20,779 siRNAs. We identified and validated several enzymes required for HCV replication, including class III phosphatidylinositol 4-kinases (PI4KA and PI4KB), carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), and mevalonate (diphospho) decarboxylase. Knockdown of PI4KA could inhibit the replication and/or HCV RNA levels of the two subgenomic genotype 1b clones (SG-1b and Luc-1b), two subgenomic genotype 1a clones (SG-1a and Luc-1a), JFH-1 genotype 2a infectious virus (JFH1-2a), and the genomic genotype 1a (FL-1a) replicon. In contrast, PI4KB knockdown inhibited replication and/or HCV RNA levels of Luc-1b, SG-1b, and Luc-1a replicons. The small molecule inhibitor, PIK93, was found to block subgenomic genotype 1b (Luc-1b), subgenomic genotype 1a (Luc-1a), and genomic genotype 2a (JFH1-2a) infectious virus replication in the nanomolar range. PIK93 was characterized by using quantitative chemical proteomics and in vitro biochemical assays to demonstrate PIK93 is a bone fide PI4KA and PI4KB inhibitor. Our data demonstrate that genetic or pharmacological modulation of PI4KA and PI4KB inhibits multiple genotypes of HCV and represents a novel druggable class of therapeutic targets for HCV infection. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1128/jvi.02418-08 |
| DOI: |
10.1128/JVI.02418-08 |
| Availability: |
https://doi.org/10.1128/jvi.02418-08; https://journals.asm.org/doi/pdf/10.1128/JVI.02418-08 |
| Rights: |
https://journals.asm.org/non-commercial-tdm-license |
| Accession Number: |
edsbas.D2C518BD |
| Database: |
BASE |