C型肝炎病毒核心蛋白調控組蛋白甲基化酵素及其下游基因表現之分子機制探討
Functional Regulation of Histone Methyltransferases and the Downstream Genes by HCV Core Protein
Date Issued
2006
Date
2006
Author(s)
Lin, Chia-Hui
DOI
en-US
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis and hepatocellular carcinoma, especially in Taiwan. However, the detailed pathogenic mechanism remains unclear. It has been reported that core protein, a structure protein of HCV, regulates several cellular signaling pathways and transcriptional factors and induces hepatocellular carcinoma in transgenic mice. Thus, the interaction between core protein and its cellular targets may play important roles in the pathogenesis. Here, we characterize HCV core protein-mediated functional regulation of histone mehtyltransferases (HMTs). HMTs belong to members of chromatin modifiers that have to be recruited by specific transcription factors to the promoter region of genes to achieve transcriptional activation or repression.
By performing in vitro HMT assays, we found that core protein represses the HMT activity of arginine-specific HMTs (R-HMTs) CARM1 and PRMT1 as well as lysine-specific HMT (K-HMT) SET9 on their target sites of histone H3 or H4. In contrast, core protein increases SET9 activity on histone H1. Interestingly, core protein itself can be methylated by CARM1 and PRMT1 in the presence of histones. By using deletion mutants in HMT assays, amino acids 51 to 101 of core protein seem to be the inhibitory domain on HMT. Core protein has been reported to regulate functions of cellular transcription factors, such as p53 and NF-κB. DNA affinity protein assays show that core protein is recruited to the NF-κB binding site, and the promoter activities of certain NF-κB target genes, Cox-2, IL-8, MCP-1 and RANTES, are reduced in the presence of core protein in HuH-7 cells. CARM1 has been reported as a novel coactivator of NF-κB. Our GST pull-down assay shows that full length core interacts with endogenous NF-κB p65 subunit, CARM1 and SET9. Moreover, CARM1, PRMT1 and SET9 have been reported to be coactivators of p53. The promoter activity of another core protein target, p53 downstream gene p21, is also repressed in the presence of core protein in HuH-7 cells, and the result of chromatin immunoprecipitation shows that core protein reduces CARM1-mediated histone H3 dimethylation at R2 and R17 and PRMT1-mediated histone H4 R3 dimethylation on p21 promoter in HuH-7 cells.
Taken together, HCV core protein-mediated downregulation of NF-κB and p53 target genes may likely occur through repression of activities of p53 and NF-κB coactivators, CARM1, PRMT1 and SET9 on histone H3/H4 methylation. Our study provides a novel pathway of core protein to modulate the activities of NF-κB and p53. And likely more HMT-regulated effects could be modulated by core protein.
Subjects
C型肝炎
核心蛋白
組蛋白甲基化酵素
hepatitis C virus
HCV
core protein
histone methyltransferase
SDGs
Type
other
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