NS3 protein of hepatitis C virus associates with the tumour suppressor p53 and inhibits its function in an NS3 sequence-dependent manner

Lin Deng, Motoko Nagano-Fujii, Motofumi Tanaka, Yuki Nomura-Takigawa, Masanori Ikeda, Nobuyuki Kato, Kiyonao Sada, Hak Hotta

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Abstract

The N-terminal 198 residues of NS3 (NS3-N) of Hepatitis C virus (HCV) subtype 1 b obtained from 29 patients, as well as full-length NS3 (NS3-Full), were analysed for their subcellular localization, interaction with the tumour suppressor p53 and serine protease activity in the presence and absence of the viral cofactor NS4A. Based on the subcellular-localization patterns in the absence of NS4A, NS3-N sequences were classified into three groups, with each group exhibiting either dot-like, diffuse or a mixed type of localization. Chimeric NS3-Full sequences, each consisting of an individual NS3-N and a shared C-terminal sequence, showed the same localization patterns as those of the respective NS3-N. Site-directed mutagenesis experiments revealed that a single or a few amino acid substitutions at a particular position(s) of NS3-N altered the localization pattern. Interestingly, NS3 of the dot-like type, either NS3-N or NS3-Full, interacted with p53 more strongly than that of the diffuse type, in both the presence and the absence of NS4A. Moreover, NS3-N of the dot-like type suppressed trans-activating activity of p53 more strongly than that of the diffuse type. Serine protease activity did not differ significantly between the two types of NS3. In HCV RNA replicon-harbouring cells, physical interaction between NS3 and p53 was observed consistently and p53-mediated transcriptional activation was suppressed significantly compared with HCV RNA-negative control cells. Our results collectively suggest the possibility that NS3 plays an important role in the hepatocarcinogenesis of HCV by interacting differentially with p53 in an NS3 sequence-dependent manner.

Original languageEnglish
Pages (from-to)1703-1713
Number of pages11
JournalJournal of General Virology
Volume87
Issue number6
DOIs
Publication statusPublished - Jun 2006

ASJC Scopus subject areas

  • Virology

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    Deng, L., Nagano-Fujii, M., Tanaka, M., Nomura-Takigawa, Y., Ikeda, M., Kato, N., Sada, K., & Hotta, H. (2006). NS3 protein of hepatitis C virus associates with the tumour suppressor p53 and inhibits its function in an NS3 sequence-dependent manner. Journal of General Virology, 87(6), 1703-1713. https://doi.org/10.1099/vir.0.81735-0