Effects of HOIL-1 ubiquitin ligase complex on the physiological function of hepatitis B virus X protein

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In the course of studies on iron-dependent degradation of iron regulatory protein 2 (IRP2), we identified a RING-type ubiquitin ligase, HOIL-1, that specifically ubiquitinates heme-oxidized IRP2. HOIL-1 had also been characterized as a hepatitis B virus X protein (HBx)-associating protein, although its function was unrevealed. We showed that HOIL-1 associates with HBx through its ubiquitin-like domain, resulting in the partial suppression of transactivation activity. Recently, we further found that HOIL-1 forms a high molecular mass complex with another uncharacterized RING-type containing protein. To investigate the role of HOIL-1 ligase complex on the pathogenesis of hepatitis B virus, we analyzed the effect of HOIL-1 complex on the transactivation activity of HBx. In HepG2 cells, co-expression of HOIL-1 complex with HBx caused to drastic increase (>10-fold) in 6x NF-κB-luciferase (Luc) reporter activity, although Rous sarcoma virus (RSV)-Luc activity was unaffected, suggesting that HBx specifically activates NF-κB pathway through the association with HOIL-1 complex. HOIL-1 complex lacking ubiquitin ligase activity had little effect on the NF-κB-Luc activity of HBx. These results suggested that HBx associates with the HOIL-1 ubiquitin ligase complex and that induces an aberrant activation of NF-κB pathway through ubiquitination activity. The mechanism might play an important role on the hepatocarcinogenesis by hepatitis B virus.