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Background <p>Hepatitis B virus (HBV) infection is a major health problem with hundreds of millions of people still chronically infected worldwide. Although it is known that cytokines can inhibit HBV replication in infected hepatocytes, much is still unknown about the underlying mechanisms or mediators.</p> Methods <p>In this study, we systematically analyzed tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) induced proteins by proteomic analysis and identified interferon-inducible protein 35 (IFI35) as a novel host restriction factor for HBV replication.</p> Results <p>Overexpression of IFI35 suppressed HBV transcription, while its reduction showed the opposite effect. Mechanistically, IFI35 regulated the stability of hepatocyte nuclear factor 4α (HNF4α), which is essential for cccDNA transcription. IFI35 did not regulate the transcription of HNF4α but rather promoted its degradation. We found that IFI35 recruits tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin-protein ligase, for K48-linked ubiquitination of HNF4α. Results were further validated using patient-derived primary human hepatocytes (PHHs) and mouse model of HBV infection. Our results revealed that cytokines, especially IFN-γ, induced IFI35 in hepatocytes. IFI35 promoted the degradation of HNF4α via the TRIM21-mediated ubiquitination, which, in turn, leads to the suppression of cccDNA transcription and viral replication.</p> Conclusions <p>Our findings demonstrate that IFI35-TRIM21-HNF4α axis may play a crucial role in TNF-α and IFN-γ induced suppression of HBV. Consequently, these results reveal a novel antiviral action of IFI35 against HBV. These findings may hold value in the development of alternative anti-HBV drugs.</p>

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IFI35 suppresses the transcription of hepatitis B virus cccDNA minichromosome via promoting HNF4α proteasomal degradation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月30日

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  • Nayeon Kim,
  • Jae Jin Shin,
  • Jae Won Oh,
  • Juhee Won,
  • Ah Ram Lee,
  • Mehrangiz Dezhbord,
  • Jeongwoo Park,
  • Ki-Young Lee,
  • Dong-Sik Kim,
  • Kwang Pyo Kim,
  • Kyun-Hwan Kim

摘要

Background

Hepatitis B virus (HBV) infection is a major health problem with hundreds of millions of people still chronically infected worldwide. Although it is known that cytokines can inhibit HBV replication in infected hepatocytes, much is still unknown about the underlying mechanisms or mediators.

Methods

In this study, we systematically analyzed tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) induced proteins by proteomic analysis and identified interferon-inducible protein 35 (IFI35) as a novel host restriction factor for HBV replication.

Results

Overexpression of IFI35 suppressed HBV transcription, while its reduction showed the opposite effect. Mechanistically, IFI35 regulated the stability of hepatocyte nuclear factor 4α (HNF4α), which is essential for cccDNA transcription. IFI35 did not regulate the transcription of HNF4α but rather promoted its degradation. We found that IFI35 recruits tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin-protein ligase, for K48-linked ubiquitination of HNF4α. Results were further validated using patient-derived primary human hepatocytes (PHHs) and mouse model of HBV infection. Our results revealed that cytokines, especially IFN-γ, induced IFI35 in hepatocytes. IFI35 promoted the degradation of HNF4α via the TRIM21-mediated ubiquitination, which, in turn, leads to the suppression of cccDNA transcription and viral replication.

Conclusions

Our findings demonstrate that IFI35-TRIM21-HNF4α axis may play a crucial role in TNF-α and IFN-γ induced suppression of HBV. Consequently, these results reveal a novel antiviral action of IFI35 against HBV. These findings may hold value in the development of alternative anti-HBV drugs.