Journal
CELL HOST & MICROBE
Volume 9, Issue 1, Pages 32-45Publisher
CELL PRESS
DOI: 10.1016/j.chom.2010.12.002
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Funding
- Landesstiftung Baden-Wurttemberg [P-LS-RNS/30]
- FORSYS (BMBF) [FKZ 0313923]
- German Research Foundation DFG [SFB/TRR77, Lo 1556/1-1, KFO 129/1-2]
- CellNetworks-Cluster of Excellence [EXC81]
- German National Genome Research Network NGFN (BMBF) [01GR0453]
- DFG
- FORSYS
- Ministry of Education of the Czech Republic [2B06052, MSM0021622419]
- Medical Faculty of the University of Heidelberg
- EU (EI-HCV)
- Tissue bank of the National Center for Tumor Diseases Heidelberg
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Hepatitis C virus (HCV) is a major causative agent of chronic liver disease in humans. To gain insight into host factor requirements for HCV replication, we performed a siRNA screen of the human kinome and identified 13 different kinases, including phosphatidylinositol-4-kinase III alpha (PI4KIIIa), as being required for HCV replication. Consistent with elevated levels of the PI4KIII alpha product phosphatidylinositol-4-phosphate (PI4P) detected in HCV-infected cultured hepatocytes and liver tissue from chronic hepatitis C patients, the enzymatic activity of PI4KIII alpha was critical for HCV replication. Viral nonstructural protein 5A (NS5A) was found to interact with PI4KIII alpha and stimulate its kinase activity. The absence of PI4KIII alpha activity induced a dramatic change in the ultrastructural morphology of the membranous HCV replication complex. Our analysis suggests that the direct activation of a lipid kinase by HCV NS5A contributes critically to the integrity of the membranous viral replication complex.
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