Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-kappa B.
The nonstructural protein 5A (NS5A) encoded by the human hepatitis C virus RNA genome is shown here to induce the activation of NF-kappaB and STAT-3 transcription factors from its cytoplasmic residence via oxidative stress. NS5A causes the disturbance of intracellular calcium. Ca2+ signaling triggers the elevation of reactive oxygen species in mitochondria, leading to the translocation of NF-kappaB and STAT-3 into the nucleus. Evidence is presented for the constitutive activation of STAT-3 by NS5A. In the presence of antioxidants [pyrrolidine dithiocarbamate (PDTC), N-acetyl l-cysteine (NAC)] or Ca2+ chelators (EGTA-AM, TMB-8), NS5A-induced activation of NF-kappaB and STAT-3 was eliminated. These results provide an insight into the mechanism by which NS5A can alter intracellular events relevant to liver pathogenesis associated with the viral infection.
Gong
G
G
Department of Microbiology and Program in Molecular Biology, University of Colorado Health Sciences Center, Denver 80262, USA.
Waris
G
G
Tanveer
R
R
Siddiqui
A
A
D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002614:Chelating Agents / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005707:Gallic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000502:physiology*; D017930:Genes, Reporter; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D050796:STAT3 Transcription Factor; D013859:Thiocarbamates / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D017361:Viral Nonstructural Proteins / Q000502:physiology*; D012324:RNA-Dependent RNA Polymerase
D000111:Acetylcysteine; D000975:Antioxidants; D002118:Calcium; D002614:Chelating Agents; D004268:DNA-Binding Proteins; D004533:Egtazic Acid; D005707:Gallic Acid; D008156:Luciferases; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; D013859:Thiocarbamates; D015534:Trans-Activators; D017361:Viral Nonstructural Proteins; C494086:STAT3 protein, human; C020972:pyrrolidine dithiocarbamic acid; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; C046770:EGTA acetoxymethyl ester; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase