title: HBx truncation mutants differentially modulate SREBP-1a and -1c transcription and HBV replication.
abstract: As master transcription factors for lipogenesis, sterol regulatory element-binding protein-1 (SREBP-1) has two isoforms, SREBP-1a and SREBP-1c. Hepatitis B virus X (HBx) can up-regulate the transcription of both SREBP-1a and SREBP-1c. HBx is a small protein consisting of 154 amino acids. Truncated forms of HBx, often found in the tissues after HBV infection, may have a role in the pathogenesis associated with HBV infection. In this study, we examined the effects of two HBx truncation mutants, HBx aa. 1-127 and HBx aa. 43-154, on the transcription of SREBP-1a and SREBP-1c. HBx 1-127 can up-regulate SREBP-1c, but not SREBP-1a transcription, whereas HBx 43-154 can activate SREBP-1a, but not SREBP-1c transcription. We further determined the activities of two HBV enhancers after the expression of the truncated HBx proteins. HBx 1-127 and HBx 43-154 can only up-regulate HBV enhancer I or HBV enhancer II, respectively. Knocking down SREBP-1 abrogates enhancer activation by HBx proteins, suggesting a role of SREBP-1. In addition, using HBV enhancer mutants, we found that the binding sequence for AP-1 on enhancer I is essential for its activation by HBx 1-127, whereas C/EBP and Sp1 sites are required for enhancer II activation by HBx 43-154. Finally, we showed that both HBx 1-127 and HBx 43-154 can increase HBV transcription and HBV replication dependent upon SREBP-1 because knocking down SREBP-1 abrogates the up-regulation. Furthermore, upon ectopic expression of either SREBP-1a or SREBP-1c, we showed that SREBP-1a is involved in HBV transcription and replication up-regulation by HBx 43-154, whereas SREBP-1c is involved in HBV transcription and replication up-regulation by HBx 1-127. Our results should help understand the interactions between HBV and the SREBP-1-mediated lipogenic pathway.
authors.affiliation: VIDO-InterVac and Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.affiliation: VIDO-InterVac, Veterinary Microbiology, Vaccinology and Immunotherapeutics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. Electronic address: qiang.liu@usask.ca.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
mesh_terms: D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D054334:Viral Regulatory and Accessory Proteins; D014779:Virus Replication
chemical_list: D050505:Mutant Proteins; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein
keywords: HBV enhancers; HBV replication; HBV transcription; HBx truncations; SREBP-1a and -1c