title: Transforming growth factor β-activated kinase 1 transcriptionally suppresses hepatitis B virus replication.
abstract: Hepatitis B Virus (HBV) replication in hepatocytes is restricted by the host innate immune system and related intracellular signaling pathways. Transforming growth factor β-activated kinase 1 (TAK1) is a key mediator of toll-like receptors and pro-inflammatory cytokine signaling pathways. Here, we report that silencing or inhibition of endogenous TAK1 in hepatoma cell lines leads to an upregulation of HBV replication, transcription, and antigen expression. In contrast, overexpression of TAK1 significantly suppresses HBV replication, while an enzymatically inactive form of TAK1 exerts no effect. By screening TAK1-associated signaling pathways with inhibitors and siRNAs, we found that the MAPK-JNK pathway was involved in TAK1-mediated HBV suppression. Moreover, TAK1 knockdown or JNK pathway inhibition induced the expression of farnesoid X receptor α, a transcription factor that upregulates HBV transcription. Finally, ectopic expression of TAK1 in a HBV hydrodynamic injection mouse model resulted in lower levels of HBV DNA and antigens in both liver and serum. In conclusion, our data suggest that TAK1 inhibits HBV primarily at viral transcription level through activation of MAPK-JNK pathway, thus TAK1 represents an intrinsic host restriction factor for HBV replication in hepatocytes.
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.|Institute of Virology, University Hospital of Essen, Essen, Germany.
authors.forename: Jinke
authors.initials: J
authors.lastname: Pang
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Geng
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Institute of Virology, University Hospital of Essen, Essen, Germany.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Zhanglian
authors.initials: Z
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.|Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Libo
authors.initials: L
authors.lastname: Tang
authors.affiliation: Institute of Virology, University Hospital of Essen, Essen, Germany.
authors.forename: Mengji
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Yan
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Jinlin
authors.initials: J
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D004279:DNA, Viral / Q000097:blood / Q000378:metabolism; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000378:metabolism* / Q000821:virology; D006515:Hepatitis B virus / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000821:virology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication; D000099150:Receptor, Farnesoid X-Activated; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D004279:DNA, Viral; D020930:MAP Kinase Kinase Kinases; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; D000099151:MAP Kinase Kinase Kinase 7