Glutamate dehydrogenase 1-dependent α-ketoglutarate promotes hepatitis B virus transcription by modulating histone methylations on the covalently closed circular DNA minichromosome
Background/Aims Hepatitis B virus (HBV) hijacks host cell metabolism, especially host glutamine metabolism, to support its replication. Glutamate dehydrogenase 1 (GDH1), a mitochondrial enzyme crucial for glutamine metabolism, can interact with histone demethylases to regulate gene expression throug...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Korean Association for the Study of the Liver
2025-07-01
|
| Series: | Clinical and Molecular Hepatology |
| Subjects: | |
| Online Access: | http://e-cmh.org/upload/pdf/cmh-2024-0694.pdf |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849703005917544448 |
|---|---|
| author | Sheng-Tao Cheng Wei-Xian Chen Hai-Jun Deng Xin He Hui Zhang Ming Tan Hai-Bo Yu Zhen-Zhen Zhang Ji-Hua Ren Min-Li Yang Da-Peng Zhang Zhi-Hong Li Juan Chen |
| author_facet | Sheng-Tao Cheng Wei-Xian Chen Hai-Jun Deng Xin He Hui Zhang Ming Tan Hai-Bo Yu Zhen-Zhen Zhang Ji-Hua Ren Min-Li Yang Da-Peng Zhang Zhi-Hong Li Juan Chen |
| author_sort | Sheng-Tao Cheng |
| collection | DOAJ |
| description | Background/Aims Hepatitis B virus (HBV) hijacks host cell metabolism, especially host glutamine metabolism, to support its replication. Glutamate dehydrogenase 1 (GDH1), a mitochondrial enzyme crucial for glutamine metabolism, can interact with histone demethylases to regulate gene expression through histone methylation. However, the mechanisms underlying GDH1-mediated glutamine metabolism reprogramming and the roles of key metabolites during HBV infection remain unclear. Methods Transcriptomic and metabolomic analyses of HBV-infected cell were performed. Both HBV-infected cells and humanized liver chimeric mice were used to elucidate the effect of glutamine metabolism on HBV. Results HBV infection leads to the abnormal activation of glutamine metabolism, including upregulation of key enzymes and metabolites involved in glutamine metabolism. The viral core protein (HBc) mediates the translocation of GDH1 into the nucleus, where GDH1 activates covalently closed circular DNA (cccDNA) transcription by converting glutamate to α-ketoglutarate (αKG). Mechanistically, the promoting effect of GDH1-derived αKG on cccDNA transcription is independent of its conventional role. Rather, αKG directly interacts with the lysine-specific demethylase KDM4A and enhances KDM4A demethylase activity to regulate αKG-dependent histone demethylation, controlling cccDNA transcription. Conclusions Our findings highlight the importance of glutamine metabolism in HBV transcription and suggest that glutamine deprivation is a potential strategy for silencing cccDNA transcription. |
| format | Article |
| id | doaj-art-1660af7e6fc547f0bcadd2a65fbba69c |
| institution | DOAJ |
| issn | 2287-2728 2287-285X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Korean Association for the Study of the Liver |
| record_format | Article |
| series | Clinical and Molecular Hepatology |
| spelling | doaj-art-1660af7e6fc547f0bcadd2a65fbba69c2025-08-20T03:17:26ZengKorean Association for the Study of the LiverClinical and Molecular Hepatology2287-27282287-285X2025-07-0131384186510.3350/cmh.2024.06942159Glutamate dehydrogenase 1-dependent α-ketoglutarate promotes hepatitis B virus transcription by modulating histone methylations on the covalently closed circular DNA minichromosomeSheng-Tao Cheng0Wei-Xian Chen1Hai-Jun Deng2Xin He3Hui Zhang4Ming Tan5Hai-Bo Yu6Zhen-Zhen Zhang7Ji-Hua Ren8Min-Li Yang9Da-Peng Zhang10Zhi-Hong Li11Juan Chen12 Department of Clinical Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China Department of Clinical Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China Department of Infectious Disease, Children’s Hospital of Chongqing Medical University, Chongqing, China The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China Department of Clinical Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaBackground/Aims Hepatitis B virus (HBV) hijacks host cell metabolism, especially host glutamine metabolism, to support its replication. Glutamate dehydrogenase 1 (GDH1), a mitochondrial enzyme crucial for glutamine metabolism, can interact with histone demethylases to regulate gene expression through histone methylation. However, the mechanisms underlying GDH1-mediated glutamine metabolism reprogramming and the roles of key metabolites during HBV infection remain unclear. Methods Transcriptomic and metabolomic analyses of HBV-infected cell were performed. Both HBV-infected cells and humanized liver chimeric mice were used to elucidate the effect of glutamine metabolism on HBV. Results HBV infection leads to the abnormal activation of glutamine metabolism, including upregulation of key enzymes and metabolites involved in glutamine metabolism. The viral core protein (HBc) mediates the translocation of GDH1 into the nucleus, where GDH1 activates covalently closed circular DNA (cccDNA) transcription by converting glutamate to α-ketoglutarate (αKG). Mechanistically, the promoting effect of GDH1-derived αKG on cccDNA transcription is independent of its conventional role. Rather, αKG directly interacts with the lysine-specific demethylase KDM4A and enhances KDM4A demethylase activity to regulate αKG-dependent histone demethylation, controlling cccDNA transcription. Conclusions Our findings highlight the importance of glutamine metabolism in HBV transcription and suggest that glutamine deprivation is a potential strategy for silencing cccDNA transcription.http://e-cmh.org/upload/pdf/cmh-2024-0694.pdfglutaminegdh1αkgcccdnamethylation |
| spellingShingle | Sheng-Tao Cheng Wei-Xian Chen Hai-Jun Deng Xin He Hui Zhang Ming Tan Hai-Bo Yu Zhen-Zhen Zhang Ji-Hua Ren Min-Li Yang Da-Peng Zhang Zhi-Hong Li Juan Chen Glutamate dehydrogenase 1-dependent α-ketoglutarate promotes hepatitis B virus transcription by modulating histone methylations on the covalently closed circular DNA minichromosome Clinical and Molecular Hepatology glutamine gdh1 αkg cccdna methylation |
| title | Glutamate dehydrogenase 1-dependent α-ketoglutarate promotes hepatitis B virus transcription by modulating histone methylations on the covalently closed circular DNA minichromosome |
| title_full | Glutamate dehydrogenase 1-dependent α-ketoglutarate promotes hepatitis B virus transcription by modulating histone methylations on the covalently closed circular DNA minichromosome |
| title_fullStr | Glutamate dehydrogenase 1-dependent α-ketoglutarate promotes hepatitis B virus transcription by modulating histone methylations on the covalently closed circular DNA minichromosome |
| title_full_unstemmed | Glutamate dehydrogenase 1-dependent α-ketoglutarate promotes hepatitis B virus transcription by modulating histone methylations on the covalently closed circular DNA minichromosome |
| title_short | Glutamate dehydrogenase 1-dependent α-ketoglutarate promotes hepatitis B virus transcription by modulating histone methylations on the covalently closed circular DNA minichromosome |
| title_sort | glutamate dehydrogenase 1 dependent α ketoglutarate promotes hepatitis b virus transcription by modulating histone methylations on the covalently closed circular dna minichromosome |
| topic | glutamine gdh1 αkg cccdna methylation |
| url | http://e-cmh.org/upload/pdf/cmh-2024-0694.pdf |
| work_keys_str_mv | AT shengtaocheng glutamatedehydrogenase1dependentaketoglutaratepromoteshepatitisbvirustranscriptionbymodulatinghistonemethylationsonthecovalentlyclosedcirculardnaminichromosome AT weixianchen glutamatedehydrogenase1dependentaketoglutaratepromoteshepatitisbvirustranscriptionbymodulatinghistonemethylationsonthecovalentlyclosedcirculardnaminichromosome AT haijundeng glutamatedehydrogenase1dependentaketoglutaratepromoteshepatitisbvirustranscriptionbymodulatinghistonemethylationsonthecovalentlyclosedcirculardnaminichromosome AT xinhe glutamatedehydrogenase1dependentaketoglutaratepromoteshepatitisbvirustranscriptionbymodulatinghistonemethylationsonthecovalentlyclosedcirculardnaminichromosome AT huizhang glutamatedehydrogenase1dependentaketoglutaratepromoteshepatitisbvirustranscriptionbymodulatinghistonemethylationsonthecovalentlyclosedcirculardnaminichromosome AT mingtan glutamatedehydrogenase1dependentaketoglutaratepromoteshepatitisbvirustranscriptionbymodulatinghistonemethylationsonthecovalentlyclosedcirculardnaminichromosome AT haiboyu glutamatedehydrogenase1dependentaketoglutaratepromoteshepatitisbvirustranscriptionbymodulatinghistonemethylationsonthecovalentlyclosedcirculardnaminichromosome AT zhenzhenzhang glutamatedehydrogenase1dependentaketoglutaratepromoteshepatitisbvirustranscriptionbymodulatinghistonemethylationsonthecovalentlyclosedcirculardnaminichromosome AT jihuaren glutamatedehydrogenase1dependentaketoglutaratepromoteshepatitisbvirustranscriptionbymodulatinghistonemethylationsonthecovalentlyclosedcirculardnaminichromosome AT minliyang glutamatedehydrogenase1dependentaketoglutaratepromoteshepatitisbvirustranscriptionbymodulatinghistonemethylationsonthecovalentlyclosedcirculardnaminichromosome AT dapengzhang glutamatedehydrogenase1dependentaketoglutaratepromoteshepatitisbvirustranscriptionbymodulatinghistonemethylationsonthecovalentlyclosedcirculardnaminichromosome AT zhihongli glutamatedehydrogenase1dependentaketoglutaratepromoteshepatitisbvirustranscriptionbymodulatinghistonemethylationsonthecovalentlyclosedcirculardnaminichromosome AT juanchen glutamatedehydrogenase1dependentaketoglutaratepromoteshepatitisbvirustranscriptionbymodulatinghistonemethylationsonthecovalentlyclosedcirculardnaminichromosome |