Abstract
ABSTRACT HBx is a short-lived protein whose rapid turnover is mainly regulated by ubiquitin-dependent proteasomal degradation pathways. Our prior work identified BAF155 to be one of the HBx binding partners. Since BAF155 has been shown to stabilize other members of the SWI/SNF chromatin remodelling complex by attenuating their proteasomal degradation, we proposed that BAF155 might also contribute to stabilizing HBx protein in a proteasome-dependent manner. Here we report that BAF155 protected hepatitis B virus X protein (HBx) from ubiquitin-independent proteasomal degradation by competing with the 20S proteasome subunit PSMA7 to bind to HBx. BAF155 was found to directly interact with HBx via binding of its SANT domain to the HBx region between amino acid residues 81 and 120. Expression of either full-length BAF155 or SANT domain increased HBx protein levels whereas siRNA-mediated knockdown of endogenous BAF155 reduced HBx protein levels. Increased HBx stability and steady-state level by BAF155 were attributable to inhibition of ubiquitin-independent and PSMA7-mediated protein degradation. Consequently, overexpression of BAF155 enhanced the transcriptional transactivation function of HBx, activated protooncogene expression and inhibited hepatoma cell clonogenicity. These results suggest that BAF155 plays important roles in ubiquitin-independent degradation of HBx, which may be related to the pathogenesis and carcinogenesis of HBV-associated HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common human cancers worldwide and chronic hepatitis B virus (HBV) infection is a major risk factor in the development of HCC [1]
35S-labeled BAF155 was retained only when reacted with bead-bound GST-hepatitis B virus X protein (HBx) fusion protein not with GST alone (Figure 1B), indicating that BAF155 could interact with HBx directly
These results clearly indicate that HBx could interact with BAF155
Summary
Hepatocellular carcinoma (HCC) is one of the most common human cancers worldwide and chronic hepatitis B virus (HBV) infection is a major risk factor in the development of HCC [1]. Among the 7 HBV viral proteins, hepatitis B virus X protein (HBx) appears to possess the most pathogenic potential as it can transactivate a variety of viral and cellular genes involved in gene transcription, intracellular signal transduction, genotoxic stress response, protein degradation, cell cycle control and apoptosis [2]. Like many other viral proteins, HBx expressed within the host cell is degraded by the proteasome pathway the mechanisms regulating this process remain to be fully elucidated. The ubiquitin-proteasome pathway has been suggested to affect. It has been reported that HBx may undergo degradation through a ubiquitin-independent mechanism since HBx with all six lysines mutated showing no evidence of ubiquitination was still susceptible to proteasomal degradation [4]
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