title: Type I IFN augments IL-27-dependent TRIM25 expression to inhibit HBV replication.
abstract: Hepatitis B virus (HBV) can cause chronic hepatitis B, which may lead to cirrhosis and liver cancer. Type I interferon (IFN) is an approved drug for the treatment of chronic hepatitis B. However, the fundamental mechanisms of antiviral action by type I IFN and the downstream signaling pathway are unclear. TRIM25 is an IFN-stimulated gene (ISG) that has an important role in RIG-I ubiquitination and activation. Whether TRIM25 is induced in liver cells by type I IFN to mediate anti-HBV function remains unclear. Here we report that interleukin-27 (IL-27) has a critical role in IFN-induced TRIM25 upregulation. TRIM25 induction requires both STAT1 and STAT3. In TRIM25 knockout HepG2 cells, type I IFN production was consistently attenuated and HBV replication was increased, whereas overexpression of TRIM25 in HepG2 cells resulted in elevated IFN production and reduced HBV replication. More interestingly, we found that TRIM25 expression was downregulated in HBV patients and the addition of serum samples from HBV patients could inhibit TRIM25 expression in HepG2 cells, suggesting that HBV might have involved a mechanism to inhibit antiviral ISG expression and induce IFN resistance. Collectively, our results demonstrate that type I IFN -induced TRIM25 is an important factor in inhibiting HBV replication, and the IFN-IL-27-TRIM25 axis may represent a new target for treating HBV infection.
authors.affiliation: Department of Immunology, Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin 130061, PR China.
authors.forename: Guangyun
authors.initials: G
authors.lastname: Tan
authors.affiliation: Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin 130021, PR China.
authors.forename: Qingfei
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Department of Immunology, Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin 130061, PR China.
authors.forename: Hongxiao
authors.initials: H
authors.lastname: Song
authors.affiliation: Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, PR China.|Suzhou Institute of Systems Medicine, Suzhou, Jiangsu 215123, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ma
authors.affiliation: Department of Immunology, Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin 130061, PR China.
authors.forename: Fengchao
authors.initials: F
authors.lastname: Xu
authors.affiliation: Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, PR China.|Suzhou Institute of Systems Medicine, Suzhou, Jiangsu 215123, PR China.
authors.forename: Di
authors.initials: D
authors.lastname: Peng
authors.affiliation: Department of Obstetrics, The First Hospital, Jilin University, Changchun, Jilin 130021, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Immunology, Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin 130061, PR China.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin 130021, PR China.
authors.forename: Junqi
authors.initials: J
authors.lastname: Niu
authors.affiliation: Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin 130021, PR China.
authors.forename: Pujun
authors.initials: P
authors.lastname: Gao
authors.affiliation: Department of Immunology, Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin 130061, PR China.|Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, PR China.|Suzhou Institute of Systems Medicine, Suzhou, Jiangsu 215123, PR China.
authors.forename: F Xiao-Feng
authors.initials: FX
authors.lastname: Qin
authors.affiliation: Department of Immunology, Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin 130061, PR China.|Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, PR China.|Suzhou Institute of Systems Medicine, Suzhou, Jiangsu 215123, PR China.|Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
mesh_terms: D000328:Adult; D005260:Female; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000628:therapy; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D057131:Immune Evasion; D007370:Interferon Type I / Q000378:metabolism* / Q000627:therapeutic use; D064094:Interleukin-27 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000070584:Tripartite Motif Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014779:Virus Replication
chemical_list: D007370:Interferon Type I; D064094:Interleukin-27; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; C084523:TRIM25 protein, human; D044767:Ubiquitin-Protein Ligases