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

초록

BackgroundHepatitis 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.MethodsIn this study, we systematically analyzed tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) induced proteins by proteomic analysis and identified interferon-inducible protein 35 (IFI35) as a novel host restriction factor for HBV replication.ResultsOverexpression of IFI35 suppressed HBV transcription, while its reduction showed the opposite effect. Mechanistically, IFI35 regulated the stability of hepatocyte nuclear factor 4 alpha (HNF4 alpha), which is essential for cccDNA transcription. IFI35 did not regulate the transcription of HNF4 alpha 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 HNF4 alpha. Results were further validated using patient-derived primary human hepatocytes (PHHs) and mouse model of HBV infection. Our results revealed that cytokines, especially IFN-gamma, induced IFI35 in hepatocytes. IFI35 promoted the degradation of HNF4 alpha via the TRIM21-mediated ubiquitination, which, in turn, leads to the suppression of cccDNA transcription and viral replication.ConclusionsOur findings demonstrate that IFI35-TRIM21-HNF4 alpha axis may play a crucial role in TNF-alpha and IFN-gamma 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.

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