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1Hepatitis C virus NS5A protein modulates c-Jun N-terminal kinase through interaction with tumor necrosis factor receptor-associated factor 2.

The nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) is a phosphoprotein possessing various functions. We have previously reported that the HCV NS5A protein interacts with tumor necrosis factor (TNF) receptor-associated factor (TRAF) domain of TRAF2 (Park, K.-J., Choi, S.-H., Lee, S. Y., Hwang, S. B., and Lai, M. M. C. (2002) J. Biol. Chem. 277, 13122-13128). Both TNF-alpha- and TRAF2-mediated nuclear factor-kappaB (NF-kappaB) activations were inhibited by NS5A-TRAF2 interaction. Because TRAF2 is required for the activation of both NF-kappaB and c-Jun N-terminal kinase (JNK), we investigated HCV NS5A protein for its potential capacity to modulate TRAF2-mediated JNK activity. Using in vitro kinase assay, we have found that NS5A protein synergistically activated both TNF-alpha- and TRAF2-mediated JNK in human embryonic kidney 293T cells. Furthermore, synergism of NS5A-mediated JNK activation was inhibited by dominant-negative form of MEK kinase 1. Our in vivo binding data show that NS5A does not inhibit interaction between TNF receptor-associated death domain and TRAF2 protein, indicating that NS5A and TRAF2 may form a ternary complex with TNF receptor-associated death domain. These results indicate that HCV NS5A protein modulates TNF signaling of the host cells and may play a role in HCV pathogenesis.

Pubmed ID: 12796506

Authors

  • Park KJ
  • Choi SH
  • Choi DH
  • Park JM
  • Yie SW
  • Lee SY
  • Hwang SB

Journal

The Journal of biological chemistry

Publication Data

August 15, 2003

Associated Grants

None

Mesh Terms

  • Cell Line
  • Gene Expression
  • Genes, Dominant
  • Hepacivirus
  • Hepatitis C
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Kidney
  • MAP Kinase Kinase Kinase 1
  • Mitogen-Activated Protein Kinases
  • Mutation
  • Protein-Serine-Threonine Kinases
  • Proteins
  • Signal Transduction
  • TNF Receptor-Associated Factor 1
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha
  • Viral Nonstructural Proteins
  • Virulence