Krüppel-like factor 15 activates hepatitis B virus gene expression and replication

Zhou, Jie; Tan, Thomas; Tian, Yongjun; Zheng, Bo‐Jian; Ou, Jing-Hsiung; Huang, Eric J.; Yen, T. S. Benedict

doi:10.1002/hep.24362

Cited by 26 publications

(25 citation statements)

References 37 publications

(50 reference statements)

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“…KLFs are expressed in multiple tissues and regulate the expression of genes involved in glucose uptake and adipogenesis [31], [32]. KLF3 is an important regulator of several biological processes, including adipogenesis, erythropoiesis, and B cell development [33]; while, KLF15 was proposed for the regulation of the HBV gene expression and replication [34]. The role of KLF15 on HBV replication was confirmed by our experimental data.…”

Section: Discussionsupporting

confidence: 71%

Lymphocytes as Liver Damage Mirror of HCV Related Adipogenesis Deregulation

Minutolo

Conti

Grelli³

et al. 2014

PLoS ONE

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Hepatitis C virus infection leads to a wide spectrum of liver diseases ranging from mild chronic hepatitis to end-stage cirrhosis and hepatocellular carcinoma. An intriguing aspect of the HCV infection is its close connection with lipid metabolism playing an important role in the HCV life cycle and in its pathogenesis. HCV is known to be a hepatotropic virus; however, it can also infect peripheral blood mononuclear cells (PBMCs). The goal of the current investigation is to compare the adipogenesis profile of liver tissues to lymphocytes of HCV infected patients, in order to understand if PBMCs may reflect the alterations of intracellular pathways occurring during HCV-related liver steatosis. Using the Human Adipogenesis PCR Array, gene expression was analyzed in liver samples and PBMCs of chronic HCV+, HBV+ and Healthy Donors (HDs) patients. We observed a similar modulation of lipid metabolism in HCV+ and HBV+liver tissues and lymphoid, cells suggesting that PBMCs reflect the liver adipogenesis deregulation related to infection, even if the two viruses have a different impact in the regulation of the adipogenesis mechanisms. In particular, some genes involved in lipid metabolism and inflammation, as well as in cell transformation, were up-regulated, in a similar way, in both HCV models analyzed. Interestingly, these genes were positively correlated to virological and hepatic functional parameters of HCV+ patients. On the contrary, HBV+ patients displayed a completely different profile. PBMCs of HCV+ patients seem to be useful model to study how HCV-related lipid metabolism deregulation occurs in liver. The obtained data suggest some molecules as new possible biomarkers of HCV-related liver damage progression.

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Section: Discussionsupporting

confidence: 71%

Lymphocytes as Liver Damage Mirror of HCV Related Adipogenesis Deregulation

Minutolo

Conti

Grelli³

et al. 2014

PLoS ONE

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“…9B) and Krüpple-like factor 15 (KLF15). A recent report demonstrated that RNA interference (RNAi) knockdown of KLF15 in vitro and in vivo significantly reduced core promoter activity and core protein expression, respectively (47). It has also been reported that mutating the Sp1-1 binding site significantly reduced precore RNA (pcRNA)/pgRNA levels, which were further reduced with additional mutation of the Sp1-2 site (21).…”

Section: Vol 85 2011 Multiple Effects Of 36-nt Insertion Of Hbv Genmentioning

confidence: 99%

Characterization of the Pleiotropic Effects of the Genotype G-Specific 36-Nucleotide Insertion in the Context of Other Hepatitis B Virus Genotypes

Gutelius¹,

Li²,

Wands³

et al. 2011

J Virol

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The pregenomic RNA (pgRNA) of hepatitis B virus (HBV) serves as the messenger for both core and P proteins, with the downstream P gene translated by ribosomal leaky scanning. HBV replication begins with packaging of the pgRNA and P protein into core protein particles, followed by conversion of RNA into DNA. Genotype G has a low replication capacity due to a low pgRNA level. It has a 36-nucleotide (nt) insertion in the 5 end of the core gene, adding 12 residues to the core protein. The insertion is needed to maintain efficient core protein expression and genome replication but causes inefficient virion secretion yet high maturity of virion DNA. In the present study, we confirmed that the 36-nt insertion had similar effects on core protein expression and virion secretion when it was introduced into genotype A and D clones but no impact on virion genome maturity. Surprisingly, the insertion impaired genome replication in both genotypes. Transcomplementation assays suggest that increased efficiency of core protein translation diminishes ribosomal scanning toward the downstream P gene. Indeed, mutating the core gene Kozak sequence restored core protein to lower levels but increased replication of the insertion mutant. Similar mutations impaired replication in genotype G. On the other hand, replacement of the core promoter sequence of genotype G with genotype A sequence increased pgRNA transcription and genome replication, implicating this region in the low replication capacity of genotype G. Why the 36-nt insertion is present in genotype G but absent in other genotypes is discussed.Hepatitis B virus (HBV) is an enveloped DNA virus and the prototype of the Hepadnaviridae family. The 3.2-kb genome contains four genes: preS1/preS2/S (envelope), precore/core, polymerase (P), and X, leading to the expression of seven viral proteins: large (L), middle (M), and small (S) envelope; core and related hepatitis B e antigen (HBeAg); P; and HBx. These proteins are translated from five mRNAs: 3.5-kb precore (HBeAg), 3.5-kb pregenomic (core and P), 2.4-kb subgenomic (L), 2.1-kb subgenomic (M and S), and 0.7-kb subgenomic (HBx) (34). These mRNAs are transcribed from the covalently closed circular DNA (cccDNA) template in the nucleus and exported to the cytoplasm for protein translation. The translation initiation sites of the core and P genes are located about 80 and 500 nucleotides (nt) from the 5Ј end of the pregenomic RNA (pgRNA), respectively, leading to much more efficient translation of core protein than P protein. P protein translation from the pgRNA is believed to involve ribosomal leaky scanning of several upstream AUG codons as well as translational termination-reinitiation (4,7,12,13,23). DNA replication initiates with core protein self-assembly into core particles, with concomitant packaging of the pgRNA and the P protein.Selective packaging of pgRNA is mediated by a stem-loop structure or the ε signal, present at its 5Ј end (14). Inside the core particle the P protein synthesizes minus-strand DNA from the pgRNA template...

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“…Potential binding sites could be predicted for four cellular factors: glial cells missing homolog 1, heat shock factor 1, Kruppel-like factor (KLF15), and sterol regulatory element binding protein. Among these factors, KLF15 has been shown to activate the SP2 promoter of HBV in a previous study, but the precise binding site of KLF15 has not been defined (29). Therefore, it will be interesting to investigate whether KLF15 binds to this region and whether HNF6 can suppress the KLF15-mediated SP2 activation in future work.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Hepatitis B Virus Gene Expression and Replication by Hepatocyte Nuclear Factor 6

Hao

Liu

et al. 2015

J Virol

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Hepatitis B virus (HBV), a small enveloped DNA virus, chronically infects more than 350 million people worldwide and causes liver diseases from hepatitis to cirrhosis and liver cancer. Here, we report that hepatocyte nuclear factor 6 (HNF6), a liver-enriched transcription factor, can inhibit HBV gene expression and DNA replication. Overexpression of HNF6 inhibited, while knockdown of HNF6 expression enhanced, HBV gene expression and replication in hepatoma cells. Mechanistically, the SP2 promoter was inhibited by HNF6, which partly accounts for the inhibition on S mRNA. Detailed analysis showed that a cis element on the HBV genome (nucleotides [nt] 3009 to 3019) was responsible for the inhibition of the SP2 promoter by HNF6. Moreover, further analysis showed that HNF6 reduced viral pregenomic RNA (pgRNA) posttranscriptionally via accelerating the degradation of HBV pgRNA independent of La protein. Furthermore, by using truncated mutation experiments, we demonstrated that the N-terminal region of HNF6 was responsible for its inhibitory effects. Importantly, introduction of an HNF6 expression construct with the HBV genome into the mouse liver using hydrodynamic injection resulted in a significant reduction in viral gene expression and DNA replication. Overall, our data demonstrated that HNF6 is a novel host factor that can restrict HBV replication via both transcriptional and posttranscriptional mechanisms. IMPORTANCEHBV is a major human pathogen whose replication is regulated by host factors. Liver-enriched transcription factors are critical for many liver functions, including metabolism, development, and cell proliferation, and some of them have been shown to regulate HBV gene expression or replication in different manners. In this study, we showed that HNF6 could inhibit the gene expression and DNA replication of HBV via both transcriptional and posttranscriptional mechanisms. As HNF6 is differentially expressed in men and women, the current results may suggest a role of HNF6 in the gender dimorphism of HBV infection.

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Krüppel-like factor 15 activates hepatitis B virus gene expression and replication

Cited by 26 publications

References 37 publications

Lymphocytes as Liver Damage Mirror of HCV Related Adipogenesis Deregulation

Lymphocytes as Liver Damage Mirror of HCV Related Adipogenesis Deregulation

Characterization of the Pleiotropic Effects of the Genotype G-Specific 36-Nucleotide Insertion in the Context of Other Hepatitis B Virus Genotypes

Inhibition of Hepatitis B Virus Gene Expression and Replication by Hepatocyte Nuclear Factor 6

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