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 t ranscription factors from its cytoplasmic residence via oxidative stress. N S5A causes the disturbance of intracellular calcium. Ca2+ signaling trigger s the elevation of reactive oxygen species in mitochondria, leading to the translocation of NF-KB and STAT-3 into the nucleus. Evidence is presented f or the constitutive activation of STAT-3 by NS5A. In the presence of antiox idants [pyrrolidine dithiocarbamate (PDTC), N-acetyl L-cysteine (NAC)] or C a2+ chelators (EGTA-AM, TMB-8), NS5A-induced activation of NF-kappaB and ST AT-3 was eliminated. These results provide an insight into the mechanism by which NS5A can alter intracellular events relevant to liver pathogenesis a ssociated with the viral infection.