GDH1-dependent α-ketoglutarate promotes HBV transcription by modulating histone methylations on the cccDNA minichromosome

Cheng, Sheng-Tao; Chen, Wei-Xian; Deng, Hai-Jun; He, Xin; Zhang, Hui; Tan, Ming; Yu, Hai-Bo; Zhang, Zhen-Zhen; Ren, Ji-Hua; Yang, Min-Li; Zhang, Da-Peng; Li, Zhi-Hong; Chen, Juan

doi:.0..

Original Article

GDH1-dependent α-ketoglutarate promotes HBV transcription by modulating histone methylations on the cccDNA minichromosome

Sheng-Tao Cheng^1,2,3, Wei-Xian Chen¹, Hai-Jun Deng³, Xin He^2,3, Hui Zhang³, Ming Tan³, Hai-Bo Yu³, Zhen-Zhen Zhang⁴, Ji-Hua Ren³, Min-Li Yang³, Da-Peng Zhang³, Zhi-Hong Li³, Juan Chen^1,2,3

¹Department of Clinical Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
²State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China
³The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
⁴Department of Infectious Disease, Children's Hospital of Chongqing Medical University, Chongqing, China

Correspondence :

Juan Chen ,
Tel: +86-23-68486780, Fax: +86-23-68486780, Email: chenjuan2014@cqmu.edu.cn

Received: August 21, 2024 Revised: January 24, 2025 Accepted: January 28, 2025
*Sheng-Tao Cheng and Wei-Xian Chen contributed equally to this work.

ABSTRACT

Background
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.

KeyWords: Glutamine; GDH1; αKG; cccDNA; Methylation