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Journal of Virology, August 2007, p. 8477-8487, Vol. 81, No. 16
0022-538X/07/$08.00+0     doi:10.1128/JVI.00477-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Processing of Capsid Protein by Cathepsin L Plays a Crucial Role in Replication of Japanese Encephalitis Virus in Neural and Macrophage Cells

Yoshio Mori, Tetsuo Yamashita, Yoshinori Tanaka, Yoshimi Tsuda, Takayuki Abe, Kohji Moriishi, and Yoshiharu Matsuura^*

Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

Received 6 March 2007/ Accepted 25 May 2007

The flavivirus capsid protein not only is a component of nucleocapsids but also plays a role in viral replication. In this study, we found a small capsid protein in cells infected with Japanese encephalitis virus (JEV) but not in the viral particles. The small capsid protein was shown to be generated by processing with host cysteine protease cathepsin L. An in vitro cleavage assay revealed that cathepsin L cleaves the capsid protein between amino acid residues Lys¹⁸ and Arg¹⁹, which are well conserved among the mosquito-borne flaviviruses. A mutant JEV resistant to the cleavage of the capsid protein by cathepsin L was generated from an infectious cDNA clone of JEV by introducing a substitution in the cleavage site. The mutant JEV exhibited growth kinetics similar to those of the wild-type JEV in monkey (Vero), mosquito (C6/36), and porcine (PK15) cell lines, whereas replication of the mutant JEV in mouse macrophage (RAW264.7) and neuroblastoma (N18) cells was impaired. Furthermore, the neurovirulence and neuroinvasiveness of the mutant JEV to mice were lower than those of the wild-type JEV. These results suggest that the processing of the JEV capsid protein by cathepsin L plays a crucial role in the replication of JEV in neural and macrophage cells, which leads to the pathogenesis of JEV infection.

Published ahead of print on 6 June 2007.

Present address: Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.

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