DOCK11 and DENND2A play pivotal roles in the maintenance of hepatitis B virus in host cells

Shinichi Hashimoto; Takayoshi Shirasaki; Taro Yamashita; Sadahiro Iwabuchi; Yutaka Suzuki; Yuzuru Takamura; Yoshiaki Ukita; Shungo Deshimaru; Toshitugu Okayama; Kazuho Ikeo; Kazuyuki Kuroki; Kazunori Kawaguchi; Eishiro Mizukoshi; Kouji Matsushima; Masao Honda; Shuichi Kaneko

doi:10.1371/journal.pone.0246313

DOCK11 and DENND2A play pivotal roles in the maintenance of hepatitis B virus in host cells

PLoS One. 2021 Feb 4;16(2):e0246313. doi: 10.1371/journal.pone.0246313. eCollection 2021.

Authors

Shinichi Hashimoto^{1

2}, Takayoshi Shirasaki³, Taro Yamashita³, Sadahiro Iwabuchi^{1

2}, Yutaka Suzuki⁴, Yuzuru Takamura⁵, Yoshiaki Ukita⁶, Shungo Deshimaru⁷, Toshitugu Okayama⁸, Kazuho Ikeo⁸, Kazuyuki Kuroki³, Kazunori Kawaguchi³, Eishiro Mizukoshi³, Kouji Matsushima⁷, Masao Honda³, Shuichi Kaneko³

Affiliations

¹ Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan.
² Japan Science and Technology Agency, CREST, Tokyo, Japan.
³ Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Ishikawa, Japan.
⁴ Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
⁵ Department of Bioscience and Biotechnology, Japan Advanced Institute of Science and Technology, Ishikawa, Japan.
⁶ Faculty of Engineering, Graduate Faculty of Interdisciplinary Research, University of Yamanashi, Yamanashi, Japan.
⁷ Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute of Biomedical Sciences, Tokyo University of Science, Noda, Japan.
⁸ Laboratory of DNA Data Analysis, National Institute of Genetics, Shizuoka, Japan.

Abstract

Human hepatitis B virus (HBV) infection remains a serious health problem worldwide. However, the mechanism for the maintenance of HBV in a latent state within host cells remains unclear. Here, using single-cell RNA sequencing analysis, we identified four genes linked to the maintenance of HBV in a liver cell line expressing HBV RNA at a low frequency. These genes included DOCK11 and DENND2A, which encode small GTPase regulators. In primary human hepatocytes infected with HBV, knockdown of these two genes decreased the amount of both HBV DNA and covalently closed circular DNA to below the limit of detection. Our findings reveal a role for DOCK11 and DENND2A in the maintenance of HBV.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Base Sequence
DNA, Viral / genetics
Guanine Nucleotide Exchange Factors / metabolism
Hep G2 Cells
Hepatitis B / metabolism*
Hepatitis B / physiopathology
Hepatitis B virus / pathogenicity
Hepatocytes / metabolism*
Hepatocytes / virology
Host Microbial Interactions / genetics*
Host Microbial Interactions / physiology
Humans
Latent Infection / physiopathology
Liver / pathology
Liver / virology
Primary Cell Culture
Single-Cell Analysis
Virus Replication / genetics

Substances

DNA, Viral
Guanine Nucleotide Exchange Factors

Grants and funding

The author(s) received specific funding for this work. This research was supported in part by the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), and by the Japan Agency for Medical Research and Development (AMED). In addition, this research was partially supported by the Program on the Innovative Development and the Application of New Drugs for Hepatitis B from AMED under Grant Number 20fk0310110.