Hepatocystin contributes to interferon-mediated antiviral response to hepatitis B virus by regulating hepatocyte nuclear factor 4α.
Hepatocystin/80K-H is known as a causative gene for autosomal dominant polycystic liver disease. However, the role of hepatocystin in hepatitis B virus-related liver disease remains unknown. Here, we investigated the role of hepatocystin on the cytokine-mediated antiviral response against hepatitis B virus infection. We investigated the antiviral effect and mechanism of hepatocystin by ectopic expression and RNAi knockdown in cell culture and mouse livers. Hepatocystin suppressed the replication of hepatitis B virus both in vitro and in vivo. This inhibitory effect was HBx-independent and mediated by the transcriptional regulation of viral genome via the activation of exogenous signal-regulated kinase 1/2 and the reduced expression of hepatocyte nuclear factor 4α, a transcription factor essential for hepatitis B virus replication. The amino-terminal region of hepatocystin was essential for regulation of this antiviral signaling pathway. We also found that hepatocystin acts as a critical component in interferon-mediated mitogen-activated protein kinase signaling pathway, and the interferon-induced antiviral activity against hepatitis B virus is associated with the expression levels of hepatocystin. We demonstrated that hepatocystin plays a critical role in modulating the susceptibility of hepatitis B virus to interferon, suggesting that the modulation of hepatocystin expression is important for cytokine-mediated viral clearance during hepatitis B virus infection.
Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea; Institute of Functional Genomics, Konkuk University, Seoul, Republic of Korea.
Gu-Choul
GC
Shin
Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
Sung Hyun
SH
Ahn
Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
Hyo-Sun
HS
Choi
Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
Jingyeong
J
Kim
Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
Eun-Sook
ES
Park
Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
Doo Hyun
DH
Kim
Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea; Institute of Functional Genomics, Konkuk University, Seoul, Republic of Korea; Research Institute of Medical Sciences, Konkuk University, Seoul, Republic of Korea. Electronic address: khkim10@kku.ac.kr.
Kyun-Hwan
KH
Kim
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D015152:Blotting, Northern; D015139:Blotting, Southern; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D002478:Cells, Cultured; D004357:Drug Synergism; D005786:Gene Expression Regulation; D005959:Glucosidases / Q000235:genetics / Q000378:metabolism*; D006509:Hepatitis B / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D006515:Hepatitis B virus / Q000472:pathogenicity; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction; D014779:Virus Replication
D000998:Antiviral Agents; D002135:Calcium-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C512949:Prkcsh protein, mouse; D007371:Interferon-gamma; D005959:Glucosidases; C070368:PRKCSH protein, human
HNF4α; Hepatitis B virus; Hepatocystin; Interferon; MAPK