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2 Publications visible to you, out of a total of 2
Identification of HNRNPK as regulator of hepatitis C virus particle production

Abstract (Expand)

Hepatitis C virus (HCV) is a major cause of chronic liver disease affecting around 130 million people worldwide. While great progress has been made to define the principle steps of the viral life cycle, … detailed knowledge how HCV interacts with its host cells is still limited. To overcome this limitation we conducted a comprehensive whole-virus RNA interference-based screen and identified 40 host dependency and 16 host restriction factors involved in HCV entry/replication or assembly/release. Of these factors, heterogeneous nuclear ribonucleoprotein K (HNRNPK) was found to suppress HCV particle production without affecting viral RNA replication. This suppression of virus production was specific to HCV, independent from assembly competence and genotype, and not found with the related Dengue virus. By using a knock-down rescue approach we identified the domains within HNRNPK required for suppression of HCV particle production. Importantly, HNRNPK was found to interact specifically with HCV RNA and this interaction was impaired by mutations that also reduced the ability to suppress HCV particle production. Finally, we found that in HCV-infected cells, subcellular distribution of HNRNPK was altered; the protein was recruited to sites in close proximity of lipid droplets and colocalized with core protein as well as HCV plus-strand RNA, which was not the case with HNRNPK variants unable to suppress HCV virion formation. These results suggest that HNRNPK might determine efficiency of HCV particle production by limiting the availability of viral RNA for incorporation into virions. This study adds a new function to HNRNPK that acts as central hub in the replication cycle of multiple other viruses.

Authors: M. Poenisch, P. Metz, H. Blankenburg, A. Ruggieri, J. Y. Lee, D. Rupp, I. Rebhan, K. Diederich, L. Kaderali, F. S. Domingues, M. Albrecht, V. Lohmann, H. Erfle, R. Bartenschlager

Date Published: 8th Jan 2015

Publication Type: Not specified

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

Abstract (Expand)

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 (PI4KIIIalpha), as being required for HCV replication. Consistent with elevated levels of the PI4KIIIalpha product phosphatidylinositol-4-phosphate (PI4P) detected in HCV-infected cultured hepatocytes and liver tissue from chronic hepatitis C patients, the enzymatic activity of PI4KIIIalpha was critical for HCV replication. Viral nonstructural protein 5A (NS5A) was found to interact with PI4KIIIalpha and stimulate its kinase activity. The absence of PI4KIIIalpha 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.

Authors: S. Reiss, I. Rebhan, P. Backes, I. Romero-Brey, H. Erfle, P. Matula, L. Kaderali, M. Poenisch, H. Blankenburg, M. S. Hiet, T. Longerich, S. Diehl, F. Ramirez, T. Balla, K. Rohr, A. Kaul, S. Buhler, R. Pepperkok, T. Lengauer, M. Albrecht, R. Eils, P. Schirmacher, V. Lohmann, R. Bartenschlager

Date Published: 18th Jan 2011

Publication Type: Not specified

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