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Recruitment and activation of a lipid kinase by NS5A of the hepatitis C virus is essential for integrity of the membranous replication compartment

Reiss, Simon and Rebhan, Ilka and Backes, Perdita and Romero-Brey, Ines and Erfle, Holger and Matula, Petr and Kaderali, Lars and Poenisch, Marion and Blankenburg, Hagen and Hiet, Marie-Sophie and Longerich, Thomas and Diehl, Sarah and Ramirez, Fidel and Rohr, Karl and Kaul, Artur and Buehler, Sandra and Pepperkok, Rainer and Lengauer, Thomas and Albrecht, Mario and Eils, Roland and Schirmacher, Peter and Lohmann, Volker and Bartenschlager, Ralf (2011) Recruitment and activation of a lipid kinase by NS5A of the hepatitis C virus is essential for integrity of the membranous replication compartment. Cell Host & Microbe, 9 (1). pp. 32-45. ISSN 19313128

Abstract

Hepatitis C virus (HCV) is the causative agent of chronic liver disease affecting 170 million individuals. To gain insight into host factor requirements of this important human pathogen we performed an siRNA screen of the human kinome. We identified 13 different kinases involved in HCV replication, including phosphatidyl-inositol 4 kinase III alpha (PI4KIIIα). Enzymatic activity of PI4KIIIα was critical for viral replication consistent with elevated levels of phosphatidylinositole-4-phosphate (PI4P) detected in cultured hepatocytes containing replicating virus and in liver tissue of chronic hepatitis C patients. Nonstructural protein 5A (NS5A) interacts with PI4KIIIα and stimulates kinase activity. Functional role of PI4P for integrity of the membranous HCV replication complex is indicated by a dramatic change of its ultrastructural morphology in the absence of PI4KIIIα activity. Our analysis provides evidence for direct activation of a lipid kinase by a viral protein and its link to integrity of the membranous replication complex.

Item Type: Article
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46
URI: https://oak.novartis.com/id/eprint/3422

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