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Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9599-604. Epub 2001 Jul 31.

Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-kappa B.

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  • 1Department of Microbiology and Program in Molecular Biology, University of Colorado Health Sciences Center, Denver 80262, USA.

Abstract

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.

PMID:
11481452
[PubMed - indexed for MEDLINE]
PMCID:
PMC55498
Free PMC Article

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