Cyclophilin A interacts with domain II of hepatitis C virus NS5A and stimulates RNA binding in an isomerase-dependent manner

Foster, Toshana L.; Gallay, Philippe; Stonehouse, Nicola J.; Harris, Mark

Abstract

NS5A plays a critical, yet poorly defined, role in hepatitis C virus genome replication. The protein consists of three domains, each of which is able to bind independently to the 3′ untranslated region (UTR) of the viral positive strand genomic RNA. The peptidyl-prolyl isomerase cyclophilin A (CypA) binds to domain II, catalyzing cis-trans isomerization. CypA inhibitors such as cyclosporine (CsA) have been shown to inhibit hepatitis C virus (HCV) replication. We show here that CypA stimulated domain II RNA binding activity, and this stimulation was abrogated by CsA. An isomerase mutant of CypA (H126Q) failed to bind to domain II and did not stimulate RNA binding. Finally, we demonstrate that the RNA binding of two domain II mutants, the D316E and D316E/Y317N mutants, previously shown to exhibit CypA independence for RNA replication, was unaffected by CypA. This study provides an insight into the molecular mechanism of CypA activity during HCV replication and further validates the use of CypA inhibitors in HCV therapy.

Citation

Foster, T. L., Gallay, P., Stonehouse, N. J., & Harris, M. (2011). Cyclophilin A interacts with domain II of hepatitis C virus NS5A and stimulates RNA binding in an isomerase-dependent manner. Journal of Virology, 85(14), 7460-7464. https://doi.org/10.1128/jvi.00393-11

• Journal Article Type: Article
• Acceptance Date: May 4, 2011
• Online Publication Date: May 18, 2011
• Publication Date: Jul 15, 2011
• Deposit Date: Mar 21, 2019
• Journal: Journal of Virology
• Print ISSN: 0022-538X
• Electronic ISSN: 1098-5514
• Publisher: American Society for Microbiology
• Peer Reviewed: Peer Reviewed
• Volume: 85
• Issue: 14
• Pages: 7460-7464
• DOI: https://doi.org/10.1128/jvi.00393-11
• Keywords: Immunology; Insect Science; Microbiology; Virology
• Public URL: https://nottingham-repository.worktribe.com/output/1673835
• Publisher URL: https://jvi.asm.org/content/85/14/7460