國家衛生研究院 NHRI:Item 3990099045/9234
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    题名: Doubly spliced RNA of hepatitis B Virus suppresses viral transcription via TATA-binding protein and induces stress granule assembly
    作者: Tsai, KN;Chong, CL;Chou, YC;Huang, CC;Wang, YL;Wang, SW;Chen, ML;Chen, CH;Chang, C
    贡献者: Institute of Molecular and Genomic Medicine
    摘要: The risk of liver cancer in patients infected with the hepatitis B virus (HBV) and their clinical response to interferon-alpha therapy vary based on HBV genotype. The mechanisms underlying these differences in HBV pathogenesis remain unclear. In HepG2 cells transfected with a mutant HBVG2335A expression plasmid that does not transcribe the 2.2-kb doubly spliced RNA (2.2DS-RNA) expressed by wild-type HBV genotype A, the level of HBV pgRNA was higher than that in cells transfected with an HBV genotype-A expression plasmid. By using co-transfection with an HBV genotype-D and 2.2DS-RNA plasmids, we found that reduction of pgRNA was observed in the cells even in low amount of the 2.2DS-RNA plasmids. Moreover, ectopic expression of 2.2DS-RNA in the HBV-producing cell line, 1.3ES2, reduced the expression of pgRNA. Further analysis showed that exogenously transcribed 2.2DS-RNA inhibited a reconstituted transcription in vitro. In Huh7 cells ectopically expressing 2.2DS-RNA, RNA immunoprecipitation revealed that 2.2DS-RNA interacted with TATA-binding protein (TBP) and that nucleotides 432 to 832 of 2.2DS-RNA were required for efficient TBP binding. Immunofluorescence experiments showed that 2.2DS-RNA colocalized with cytoplasmic TBP and the stress granule components, G3BP and PABP1, in Huh7 cells. In conclusion, our study reveals that 2.2DS-RNA acts as a repressor of HBV transcription through an interaction with TBP that induces stress granule formation. The expression of 2.2DS-RNA may be one of viral factors involved in viral replication, which may underlie differences in clinical outcomes of liver disease and response to interferon-alpha therapy between patients infected with different HBV genotypes. IMPORTANCE: Patients infected with certain genotypes of HBV have a lower risk of hepatocellular carcinoma, and exhibit a more favorable response to antiviral therapy than patients infected with other HBV genotypes. Using cultured human hepatoma cells as a model of HBV infection, we found that the expression of 2.2DS-RNA caused a decrease in HBV replication. In cultured cells, the ectopic expression of 2.2DS-RNA obviously reduced the intracellular levels of HBV mRNAs. Our analysis of the 2.2DS-RNA-mediated suppression of viral RNA expression showed that 2.2DS-RNA inhibited transcription via binding to TATA-binding protein and stress granule proteins. Our findings suggest that the 2.2DS-RNA acts as a suppressive noncoding RNA that modulates HBV replication, which may in turn influence the development of chronic hepatitis B.
    日期: 2015-11
    關聯: Journal of Virology. 2015 Nov;89(22):11406-11419.
    Link to: http://dx.doi.org/10.1128/jvi.00949-15
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-538X&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000363467200021
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84945955156
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