Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/81193
Title: Phosphatidylinositol 4,5-Bisphosphate Is an HCV NS5A Ligand and Mediates Replication of the Viral Genome
Authors: Cho, Nam-Joon
Lee, Choongho
Pang, Phillip S.
Pham, Edward A.
Fram, Benjamin
Nguyen, Khanh
Xiong, Anming
Sklan, Ella H.
Elazar, Menashe
Koytak, Elif S.
Kersten, Caroline
Kanazawa, Kay K.
Frank, Curtis W.
Glenn, Jeffrey S.
Keywords: QCM
Antiviral Strategies
Signaling Molecule
Phospholipid
Issue Date: 2015
Source: Cho, N.-J., Lee, C., Pang, P. S., Pham, E. A., Fram, B., Nguyen, K., et al. (2015). Phosphatidylinositol 4,5-Bisphosphate Is an HCV NS5A Ligand and Mediates Replication of the Viral Genome. Gastroenterology, 148(3), 616-625.
Series/Report no.: Gastroenterology
Abstract: Background & Aims: Phosphoinositides (PIs) bind and regulate localization of proteins via a variety of structural motifs. PI 4,5-bisphosphate (PI[4,5]P2) interacts with and modulates the function of several proteins involved in intracellular vesicular membrane trafficking. We investigated interactions between PI(4,5)P2 and hepatitis C virus (HCV) nonstructural protein 5A (NS5A) and effects on the viral life cycle. Methods: We used a combination of quartz crystal microbalance, circular dichroism, molecular genetics, and immunofluorescence to study specific binding of PI(4,5)P2 by the HCV NS5A protein. We evaluated the effects of PI(4,5)P2 on the function of NS5A by expressing wild-type or mutant forms of Bart79I or FL-J6/JFH-5’C19Rluc2AUbi21 RNA in Huh7 cells. We also studied the effects of strategies designed to inhibit PI(4,5)P2 on HCV replication in these cells. Results: The N-terminal amphipathic helix of NS5A bound specifically to PI(4,5)P2, inducing a conformational change that stabilized the interaction between NS5A and TBC1D20, which is required for HCV replication. A pair of positively charged residues within the amphipathic helix (the basic amino acid PI(4,5)P2 pincer domain) was required for PI(4,5)P2 binding and replication of the HCV-RNA genome. A similar motif was found to be conserved across all HCV isolates, as well as amphipathic helices of many pathogens and apolipoproteins. Conclusions: PI(4,5)P2 binds to HCV NS5A to promote replication of the viral RNA genome in hepatocytes. Strategies to disrupt this interaction might be developed to inhibit replication of HCV and other viruses.
URI: https://hdl.handle.net/10356/81193
http://hdl.handle.net/10220/40671
ISSN: 0016-5085
DOI: 10.1053/j.gastro.2014.11.043
Rights: © 2015 American Gastroenterological Association (Published by Elsevier).
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:SCBE Journal Articles

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