Hepatitis C virus induced suppression of IκBζ and interference with IκBζ induced Lipocalin2 Expression

Every year, 3 – 4 million people are infected with the Hepatitis C virus (HCV). In more than 70% the infection becomes chronic and leads to complications like liver failure, end stage cirrhosis or Hepatocellular Carcinoma. More than 350 000 people die every year from HCV. In recent years it became more and more evident that HCV broadly interacts with key pathways of its host cell and has evolved strategies to influence processes such as cell proliferation, cell differentiation, apoptosis but also the intercellular communication within its host.

One of these key pathways influenced by the virus are signal-transduction pathways that depend on activation of the transcription factor NFκB. These pathways are controlled by IκB-proteins, which to a major part represent endogenous inhibitors that bind to NFκB and trap it in the cytoplasm. This function is mainly provided by so termed typical IκB's like IκBα or IκBβ, which upon stimulation become degraded and release NFκB. Subsequently NFκB translocates to the nucleus, where it regulates the transcription of its target genes. Contrariwise, untypical IκB-proteins such as IκBζ are induced upon stimulation and remain in the nucleus where it acts as an NFκB-inhibitor but also as a transcriptional regulator of a variety of different genes. In human hepatocytes IκBζ is induced upon stimulation with IL-1β but not with TNFα. The present study provides evidence that in hepatocytes and hepatoma cell lines down-regulation of IL-1β-induced IκBζ protein levels back to baseline occurs via proteasomal degradation. In contrast to this, inhibition of IL-1β-induced expression of IkBζ by HCV occurs via enhanced Calpain-dependent degradation but does not involve proteasomal degradation. Most interestingly Lipocalin-2, a glycoprotein that plays a role for iron transport, as a suppressor of bacterial growth and inductor of apoptotic cell death, has been identified as a target gene which is suppressed by HCV as its expression is IκBζ-dependently regulated by IL-1β. In conclusion, evidence is provided that in hepatocytes under normal conditions down-regulation of IκBζ protein levels induced by IL-1β occurs via proteasomal degradation while the suppression of IL-1β-induced LCN-2 expression by HCV involves Calpain-dependent degradation of the transcriptional regulator IκBζ.