title: 1Hepatitis C virus NS5A protein modulates c-Jun N-terminal kinase through interaction with tumor necrosis factor receptor-associated factor 2.
abstract: 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.
authors.affiliation: Ilsong Institute of Life Science, Hallym University, Chuncheon 200-702, Korea.
authors.forename: Kyu-Jin
authors.initials: KJ
authors.lastname: Park
authors.forename: Soo-Ho
authors.initials: SH
authors.lastname: Choi
authors.forename: Dong-Hwa
authors.initials: DH
authors.lastname: Choi
authors.forename: Jung-Min
authors.initials: JM
authors.lastname: Park
authors.forename: Se Won
authors.initials: SW
authors.lastname: Yie
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Soon B
authors.initials: SB
authors.lastname: Hwang
mesh_terms: D002460:Cell Line; D015870:Gene Expression; D005799:Genes, Dominant; D016174:Hepacivirus / Q000201:enzymology* / Q000472:pathogenicity; D006526:Hepatitis C / Q000378:metabolism / Q000821:virology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D007668:Kidney / Q000166:cytology; D048728:MAP Kinase Kinase Kinase 1; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D012324:RNA-Dependent RNA Polymerase
chemical_list: D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D017361:Viral Nonstructural Proteins; C482576:MAP3K1 protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase