title: SREBP-1a activation by HBx and the effect on hepatitis B virus enhancer II/core promoter.
abstract: Hepatitis B virus (HBV) X protein (HBx) plays an important role in HBV pathogenesis by regulating gene expression. Sterol regulatory element binding protein-1a (SREBP-1a) is a key transcriptional factor for modulating fatty acid and cholesterol synthesis. Here we demonstrated that HBx increased mature SREBP-1a protein level in the nucleus and its activity as a transcription factor. We further showed that the up-regulation of SREBP-1a by HBx occurred at the transcriptional level after ectopic expression and in the context of HBV replication. Deletional analysis using SREBP-1a promoter revealed that the sequence from -436 to -398 in the promoter was required for its activation by HBx. This promoter region possesses the binding sequences for two basic leucine zipper (b-ZIP) transcription factors, namely C/EBP and E4BP4. Mutagenesis of the binding sequences on the SREBP-1a promoter and ectopic expression experiments demonstrated that C/EBPα enhanced SREBP-1a activation by HBx, while E4BP4 had an inhibitory effect. C/EBPα was able to significantly reverse the inhibitory activity of E4BP4 on SREBP-1a promoter. These results demonstrated that HBx activates SREBP-1a activity at the transcription level through a complex mechanism involving two bZIP transcription factors C/EBP and E4BP4 with C/EBP being the dominant positive factor. Finally, we showed that knocking down SREBP-1 abolishes HBV enhancer II/core promoter activation by HBx.
authors: Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada S7N 5E3.
authors: Ling
authors: L
authors: Qiao
authors: Qi
authors: Q
authors: Wu
authors: Xinya
authors: X
authors: Lu
authors: Yan
authors: Y
authors: Zhou
authors: Ana
authors: A
authors: Fernández-Alvarez
authors: Lihong
authors: L
authors: Ye
authors: Xiaodong
authors: X
authors: Zhang
authors: Jihong
authors: J
authors: Han
authors: Marta
authors: M
authors: Casado
authors: Qiang
authors: Q
authors: Liu
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D004742:Enhancer Elements, Genetic; D015967:Gene Expression Regulation, Viral; D006509:Hepatitis B / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics*; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014758:Viral Core Proteins / Q000235:genetics; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D022762:CCAAT-Enhancer-Binding Proteins; C497440:NFIL3 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators; D014758:Viral Core Proteins; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein