Hepatitis C virus NS5A protein induces the activation of NF-kB and STAT-3 transcription factors via oxidative stress and disturbance of intracellular calcium.
HCV NS5A protein activates NF-κB and STAT-3 transcription factors through calcium-dependent oxidative stress pathways, providing insight into HCV-associated liver pathogenesis.
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 et al. (2001) studied Hepatitis C virus infection. HCV NS5A protein expression vs. Untransfected cells or mutant NS5A was evaluated on Activation of NF-kB and STAT-3 transcription factors. Hepatitis C virus NS5A protein induces the activation of NF-kB and STAT-3 transcription factors via oxidative stress and disturbance of intracellular calcium.