한빛사논문
- 조회111
성균관대학교 의과대학
Mehrangiz Dezhbord1,*, Seong Ho Kim1,*, Soree Park1, Da Rae Lee1, Nayeon Kim1, Juhee Won1,2, Ah Ram Lee1, Dong-Sik Kim3, Kyun-Hwan Kim1
1Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, Korea
2Department of Pharmacology, School of Medicine, Konkuk University, Seoul, Korea
3Department of Surgery, Division of HBP Surgery and Liver Transplantation, College of Medicine, Korea University, Seoul, Korea
Corresponding author : Kyun-Hwan Kim
*These authors contributed equally to this work.
Abstract
Background/Aims
The major histocompatibility class II (MHC II) transactivator, known as CIITA, is induced by Interferon gamma (IFN-γ) and plays a well-established role in regulating the expression of class II MHC molecules in antigen-presenting cells.
Methods
Primary human hepatocytes (PHH) were isolated via therapeutic hepatectomy from two donors. The hepatocellular carcinoma (HCC) cell lines HepG2 and Huh7 were used for the mechanistic study, and HBV infection was performed in HepG2-NTCP cells. HBV DNA replication intermediates and secreted antigen levels were measured using Southern blotting and ELISA, respectively.
Results
We identified a non-canonical function of CIITA in the inhibition of hepatitis B virus (HBV) replication in both HCC cells and patient-derived PHH. Notably, in vivo experiments demonstrated that HBV DNA and secreted antigen levels were significantly decreased in mice injected with the CIITA construct. Mechanistically, CIITA inhibited HBV transcription and replication by suppressing the activity of HBV-specific enhancers/promoters. Indeed, CIITA exerts antiviral activity in hepatocytes through ERK1/2-mediated down-regulation of the expression of hepatocyte nuclear factor 1α (HNF1α) and HNF4α, which are essential factors for virus replication. In addition, silencing of CIITA significantly abolished the IFN-γ-mediated anti-HBV activity, suggesting that CIITA mediates the anti-HBV activity of IFN-γ to some extent. HBV X protein (HBx) counteracts the antiviral activity of CIITA via direct binding and impairing its function.
Conclusions
Our findings reveal a novel antiviral mechanism of CIITA that involves the modulation of the ERK pathway to restrict HBV transcription. Additionally, our results suggest the possibility of a new immune avoidance mechanism involving HBx.
논문정보
- Research article
- 2024년 07월 (BRIC 등록일 2024-07-26)
- 국내 연구진
- 의약학 > 감염의학
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