Figure 7.

Proposed HBV restriction factor models: (a) Based on results of this study, this model proposes at least two categories of HBV restriction factors. Some HBV restriction factors are already present in the CRL4^UN (green triangles), while others are recruited to the CRL4 by HBx (green squares). (b) Proposed model to explain a role for ZEB2 as an HBV restriction factor. Left, ZEB2 is a DNA binding transcriptional repressor previously shown to bind to the HBV core promoter and significantly decrease HBV transcription [73]. Right, HBx relieves ZEB2-mediated transcriptional suppression by upregulating miR146a [107], which promotes HBV replication by targeting ZEB2 [106]. In the current study, we propose that HBx utilizes the CRL4 complex to target ZEB2 for degradation. (c) Proposed mechanism for restriction factor PSME4. Left, Transcriptionally inactive cccDNA has a preponderance of hypoacetylated histones (empty circles) and associates with specific factors ((histone deacetylases (HDACs), transcriptional repressors, and methyltransferases)] such as HDAC1 and Nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase sirtuin 1 (Hsirt1) [10], yin yang 1 (YY1) and enhancer of zeste homolog 2 (Ezh2) [111], protein arginine methyltransferase 1 (PRMT1) [109], and PRMT5 [110]. Right, Alternatively, transcriptionally active cccDNA contains a preponderance of hyperacetylated histones (filled circles) and associates with other factors including cyclic adenosine monophosphate (cAMP) responsive element binding protein 1 (CREB) [108], CREB binding protein (CBP), P300, P300/CBP-associated factor (pCAF), PSME4 (red font, identified in this study) and HBx [10,11]. We propose that PSME4 is a viral restriction factor because of its ability to degrade acetylated histones [70,71], thereby helping to return cccDNA to an inactive state unless HBx is present to promote the degradation of PSME4.