Interferon-stimulated gene of 20 kDa protein (ISG20) degrades RNA of hepatitis B virus to impede the replication of HBV in vitro and in vivo.
Hepatitis B virus (HBV) barely induces host interferon (IFN)-stimulated genes (ISGs), which allows efficient HBV replication in the immortalized mouse hepatocytes as per human hepatocytes. Here we found that transfection of Isg20 plasmid robustly inhibits the HBV replication in HBV-infected hepatocytes irrespective of IRF3 or IFN promoter activation. Transfection of Isg20 is thus effective to eradicate HBV in the infected hepatocytes. Transfection of HBV genome or ε-stem of HBV pgRNA (active pgRNA moiety) failed to induce Isg20 in the hepatocytes, while control polyI:C (a viral dsRNA analogue mimic) activated MAVS pathway leading to production of type I IFN and then ISGsg20 via the IFN-α/β receptor (IFNAR). Consistently, addition of IFN-α induced Isg20 and partially suppressed HBV replication in hepatocytes. Chasing HBV RNA, DNA and proteins by blotting indicated that ISG20 expression decreased HBV RNA and replicative DNA in HBV-transfected cells, which resulted in low HBs antigen production and virus titer. The exonuclease domains of ISG20 mainly participated in HBV-RNA decay. In vivo hydrodynamic injection, ISG20 was crucial for suppressing HBV replication without degrading host RNA in the liver. Taken together, ISG20 acts as an innate anti-HBV effector that selectively degrades HBV RNA and blocks replication of infectious HBV particles. ISG20 would be a critical effector for ameliorating chronic HBV infection in the IFN therapy.
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638 Japan.|Present address: Section of Bioengineering Technology, Universiti Kuala Lumpur (UNIKL) MICET, Kuala Lumpur, 78000 Malaysia.
Chean Ring
CR
Leong
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638 Japan.
Kenji
K
Funami
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638 Japan.|Present address: Department of Immunology, Graduate School of Medical Science, Kumamoto University, Kumamoto, 860-8556 Japan.
Hiroyuki
H
Oshiumi
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638 Japan.
Deng
D
Mengao
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638 Japan.
Hiromi
H
Takaki
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638 Japan.
Misako
M
Matsumoto
Department of Virology II, National Institute of Infectious Diseases, Tokyo, 162-8640 Japan.
Hussein H
HH
Aly
Department of Virology II, National Institute of Infectious Diseases, Tokyo, 162-8640 Japan.
Koichi
K
Watashi
Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553 Japan.
Kazuaki
K
Chayama
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638 Japan.
Tsukasa
T
Seya
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D005092:Exonucleases / Q000235:genetics* / Q000378:metabolism; D005095:Exoribonucleases; D020869:Gene Expression Profiling / Q000379:methods; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000235:genetics* / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000378:metabolism / Q000821:virology; D022781:Hepatocytes / Q000378:metabolism* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020871:RNA Stability; D012367:RNA, Viral / Q000235:genetics* / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics*
D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D053633:Receptor, Interferon alpha-beta; D005092:Exonucleases; D005095:Exoribonucleases; C112346:ISG20 protein, human
ISG20; gene therapy; interferon (IFN); interferon-stimulated genes (ISGs); hepatitis B virus (HBV)