High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction

Hiromichi Dansako; Hirotaka Imai; Youki Ueda; Shinya Satoh; Kunitada Shimotohno; Nobuyuki Kato

doi:10.1096/fba.1022

High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction

Hiromichi Dansako, Hirotaka Imai, Youki Ueda, Shinya Satoh, Kunitada Shimotohno, Nobuyuki Kato

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

Abstract

Hepatitis B virus (HBV) is a hepatotropic DNA virus causing hepatic diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. To study HBV, human hepatoma HepG2 cells are currently used as an HBV infectious cell culture model worldwide. HepG2 cells exhibit susceptibility to HBV by exogenously expressing sodium taurocholate cotransporting polypeptide (NTCP). We herein demonstrated that human immortalized hepatocyte NKNT-3 cells exhibited susceptibility to HBV by exogenously expressing NTCP (NKNT-3/NTCP cells). By comparing cyclic GMP-AMP synthetase (cGAS)-stimulator of interferon genes (STING) signaling pathway in several NKNT-3/NTCP cell-derived cell clones, we found that STING was highly expressed in cell clones exhibiting resistance but not susceptibility to HBV. High-level expression of STING was implicated in HBV-triggered induction of type III IFN and a pro-inflammatory cytokine, IL-6. In contrast, RNAi-mediated knockdown of STING inhibited type III IFN induction and restored the levels of HBV total transcript in an HBV-infected cell clone exhibiting resistance to HBV. These results suggest that STING regulates susceptibility to HBV by its expression levels. STING may thus be a novel target for anti-HBV strategies.

Original language	English
Pages (from-to)	67-80
Number of pages	14
Journal	FASEB BioAdvances
Volume	1
Issue number	2
DOIs	https://doi.org/10.1096/fba.1022
Publication status	Published - Feb 2019

Keywords

STING
hepatitis B virus
hepatocellular carcinoma
host innate immune response
type III interferon

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology (miscellaneous)
Cancer Research
Molecular Medicine
Physiology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1096/fba.1022

Cite this

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title = "High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction",

abstract = "Hepatitis B virus (HBV) is a hepatotropic DNA virus causing hepatic diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. To study HBV, human hepatoma HepG2 cells are currently used as an HBV infectious cell culture model worldwide. HepG2 cells exhibit susceptibility to HBV by exogenously expressing sodium taurocholate cotransporting polypeptide (NTCP). We herein demonstrated that human immortalized hepatocyte NKNT-3 cells exhibited susceptibility to HBV by exogenously expressing NTCP (NKNT-3/NTCP cells). By comparing cyclic GMP-AMP synthetase (cGAS)-stimulator of interferon genes (STING) signaling pathway in several NKNT-3/NTCP cell-derived cell clones, we found that STING was highly expressed in cell clones exhibiting resistance but not susceptibility to HBV. High-level expression of STING was implicated in HBV-triggered induction of type III IFN and a pro-inflammatory cytokine, IL-6. In contrast, RNAi-mediated knockdown of STING inhibited type III IFN induction and restored the levels of HBV total transcript in an HBV-infected cell clone exhibiting resistance to HBV. These results suggest that STING regulates susceptibility to HBV by its expression levels. STING may thus be a novel target for anti-HBV strategies.",

keywords = "STING, hepatitis B virus, hepatocellular carcinoma, host innate immune response, type III interferon",

author = "Hiromichi Dansako and Hirotaka Imai and Youki Ueda and Shinya Satoh and Kunitada Shimotohno and Nobuyuki Kato",

note = "Funding Information: We thank Marie Iwado, Masayo Takemoto, and Masato Ono for their technical assistance. We also thank Dr. Tsuyoshi Akagi for the provision of pCX4bleo retroviral vectors. This research was supported by the Japan Agency for Medical Research and Development (AMED) under grant numbers JP18fk0310107 and JP18fk0310103, and by a grant from the Wesco Foundation. Publisher Copyright: {\textcopyright} 2018 The Authors.",

year = "2019",

month = feb,

doi = "10.1096/fba.1022",

language = "English",

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T1 - High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction

AU - Dansako, Hiromichi

AU - Imai, Hirotaka

AU - Ueda, Youki

AU - Satoh, Shinya

AU - Shimotohno, Kunitada

AU - Kato, Nobuyuki

N1 - Funding Information: We thank Marie Iwado, Masayo Takemoto, and Masato Ono for their technical assistance. We also thank Dr. Tsuyoshi Akagi for the provision of pCX4bleo retroviral vectors. This research was supported by the Japan Agency for Medical Research and Development (AMED) under grant numbers JP18fk0310107 and JP18fk0310103, and by a grant from the Wesco Foundation. Publisher Copyright: © 2018 The Authors.

PY - 2019/2

Y1 - 2019/2

N2 - Hepatitis B virus (HBV) is a hepatotropic DNA virus causing hepatic diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. To study HBV, human hepatoma HepG2 cells are currently used as an HBV infectious cell culture model worldwide. HepG2 cells exhibit susceptibility to HBV by exogenously expressing sodium taurocholate cotransporting polypeptide (NTCP). We herein demonstrated that human immortalized hepatocyte NKNT-3 cells exhibited susceptibility to HBV by exogenously expressing NTCP (NKNT-3/NTCP cells). By comparing cyclic GMP-AMP synthetase (cGAS)-stimulator of interferon genes (STING) signaling pathway in several NKNT-3/NTCP cell-derived cell clones, we found that STING was highly expressed in cell clones exhibiting resistance but not susceptibility to HBV. High-level expression of STING was implicated in HBV-triggered induction of type III IFN and a pro-inflammatory cytokine, IL-6. In contrast, RNAi-mediated knockdown of STING inhibited type III IFN induction and restored the levels of HBV total transcript in an HBV-infected cell clone exhibiting resistance to HBV. These results suggest that STING regulates susceptibility to HBV by its expression levels. STING may thus be a novel target for anti-HBV strategies.

AB - Hepatitis B virus (HBV) is a hepatotropic DNA virus causing hepatic diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. To study HBV, human hepatoma HepG2 cells are currently used as an HBV infectious cell culture model worldwide. HepG2 cells exhibit susceptibility to HBV by exogenously expressing sodium taurocholate cotransporting polypeptide (NTCP). We herein demonstrated that human immortalized hepatocyte NKNT-3 cells exhibited susceptibility to HBV by exogenously expressing NTCP (NKNT-3/NTCP cells). By comparing cyclic GMP-AMP synthetase (cGAS)-stimulator of interferon genes (STING) signaling pathway in several NKNT-3/NTCP cell-derived cell clones, we found that STING was highly expressed in cell clones exhibiting resistance but not susceptibility to HBV. High-level expression of STING was implicated in HBV-triggered induction of type III IFN and a pro-inflammatory cytokine, IL-6. In contrast, RNAi-mediated knockdown of STING inhibited type III IFN induction and restored the levels of HBV total transcript in an HBV-infected cell clone exhibiting resistance to HBV. These results suggest that STING regulates susceptibility to HBV by its expression levels. STING may thus be a novel target for anti-HBV strategies.

KW - STING

KW - hepatitis B virus

KW - hepatocellular carcinoma

KW - host innate immune response

KW - type III interferon

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ER -

High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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