Structural analysis of Hepatitis C virus core-E1 signal peptide and requirements for cleavage of the genotype 3a signal sequence by signal peptide peptidase

Oehler, V., Filipe, A., Montserret, R., da Costa, D., Brown, G., Penin, F. and McLauchlan, J. (2012) Structural analysis of Hepatitis C virus core-E1 signal peptide and requirements for cleavage of the genotype 3a signal sequence by signal peptide peptidase. Journal of Virology, 86(15), pp. 7818-7828. (doi:10.1128/JVI.00457-12) (PMID:22593157) (PMCID:PMC3421639)

Full text not currently available from Enlighten.

Abstract

The maturation of the hepatitis C virus (HCV) core protein requires proteolytic processing by two host proteases: signal peptidase (SP) and the intramembrane-cleaving protease signal peptide peptidase (SPP). Previous work on HCV genotype 1a (GT1a) and GT2a has identified crucial residues required for efficient signal peptide processing by SPP, which in turn has an effect on the production of infectious virus particles. Here we demonstrate that the JFH1 GT2a core-E1 signal peptide can be adapted to the GT3a sequence without affecting the production of infectious HCV. Through mutagenesis studies, we identified crucial residues required for core-E1 signal peptide processing, including a GT3a sequence-specific histidine (His) at position 187. In addition, the stable knockdown of intracellular SPP levels in HuH-7 cells significantly affects HCV virus titers, further demonstrating the requirement for SPP for the maturation of core and the production of infectious HCV particles. Finally, our nuclear magnetic resonance (NMR) structural analysis of a synthetic HCV JFH1 GT2a core-E1 signal peptide provides an essential structural template for a further understanding of core processing as well as the first model for an SPP substrate within its membrane environment. Our findings give deeper insights into the mechanisms of intramembrane-cleaving proteases and the impact on viral infections.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Brown, Mrs Gaie and Da Silva Filipe, Dr Ana and McLauchlan, Professor John and Oehler, Dr Verena
Authors: Oehler, V., Filipe, A., Montserret, R., da Costa, D., Brown, G., Penin, F., and McLauchlan, J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Virology
Journal Abbr.:J. Virol.
ISSN:0022-538X
ISSN (Online):1098-5514
Published Online:16 May 2012

University Staff: Request a correction | Enlighten Editors: Update this record