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Journal of Virology, September 2008, p. 8349-8361, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00306-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Intramembrane Processing by Signal Peptide Peptidase Regulates the Membrane Localization of Hepatitis C Virus Core Protein and Viral Propagation{triangledown}

Kiyoko Okamoto,1,{dagger} Yoshio Mori,1,{dagger} Yasumasa Komoda,1 Toru Okamoto,1 Masayasu Okochi,2 Masatoshi Takeda,2 Tetsuro Suzuki,3 Kohji Moriishi,1 and Yoshiharu Matsuura1*

Department of Molecular Virology, Research Institute for Microbial Diseases,1 Department of Post-Genomics and Diseases, Division of Psychiatry and Behavioral Proteomics, Graduate School of Medicine, Osaka University, Osaka,2 Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan3

Received 12 February 2008/ Accepted 11 June 2008

Hepatitis C virus (HCV) core protein has shown to be localized in the detergent-resistant membrane (DRM), which is distinct from the classical raft fraction including caveolin, although the biological significance of the DRM localization of the core protein has not been determined. The HCV core protein is cleaved off from a precursor polyprotein at the lumen side of Ala191 by signal peptidase and is then further processed by signal peptide peptidase (SPP) within the transmembrane region. In this study, we examined the role of SPP in the localization of the HCV core protein in the DRM and in viral propagation. The C terminus of the HCV core protein cleaved by SPP in 293T cells was identified as Phe177 by mass spectrometry. Mutations introduced into two residues (Ile176 and Phe177) upstream of the cleavage site of the core protein abrogated processing by SPP and localization in the DRM fraction. Expression of a dominant-negative SPP or treatment with an SPP inhibitor, L685,458, resulted in reductions in the levels of processed core protein localized in the DRM fraction. The production of HCV RNA in cells persistently infected with strain JFH-1 was impaired by treatment with the SPP inhibitor. Furthermore, mutant JFH-1 viruses bearing SPP-resistant mutations in the core protein failed to propagate in a permissive cell line. These results suggest that intramembrane processing of HCV core protein by SPP is required for the localization of the HCV core protein in the DRM and for viral propagation.

* Corresponding author. Mailing address: Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-8340. Fax: 81-6-6879-8269. E-mail: matsuura{at}biken.osaka-u.ac.jp

{triangledown} Published ahead of print on 18 June 2008.

{dagger} K. Okamoto and Y. Mori contributed equally to this work.

Journal of Virology, September 2008, p. 8349-8361, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00306-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kota, S., Coito, C., Mousseau, G., Lavergne, J.-P., Strosberg, A. D. (2009). Peptide inhibitors of hepatitis C virus core oligomerization and virus production. J. Gen. Virol. 90: 1319-1328 [Abstract] [Full Text]  


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