Multiomics interrogation into HBV (Hepatitis B virus)-host interaction reveals novel coding potential in human genome, and identifies canonical and non-canonical proteins as host restriction factors against HBV

Cell Discovery

Kun Wang¹  Chuanyin Li¹  Caiwei Jia¹  Ronggui Hu²  Shilin Yuan³  He Wang⁴  Jian Zhang⁵  Qiang Deng⁶  Yuanfei Zhu⁶  Na Sun⁷  Axel Walch⁷  Daming Gao⁸  Menghuan Zhang⁸  Guanghong Liao⁹  Ping Xu^1,10  Weidi Xiao^1,10 

[1] Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China;Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China;State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China;School of Life Science, Hangzhou Institute for Advance Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China;Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China;State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China;University of Chinese Academy of Sciences, Beijing, China;Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China;Key Laboratory of Cell Differentiation and Apoptosis, Medicinal Bioinformatics Center, Shanghai JiaoTong University School of Medicine, Shanghai, China;Key Laboratory of Medical Molecular Virology (MOE & MOH), School of Basic Medical Sciences, Fudan University, Shanghai, China;Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany;State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China;State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China;University of Chinese Academy of Sciences, Beijing, China;State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Research Unit of Proteomics & Research and Development of New Drug of Chinese Academy of Medical Sciences, Beijing Institute of Lifeomics, Beijing, China;

DOI  :  10.1038/s41421-021-00337-3

来源: Springer

【 摘 要 】

Hepatitis B Virus (HBV) constitutes a major threat to global public health. Current understanding of HBV-host interaction is yet limited. Here, ribosome profiling, quantitative mass spectrometry and RNA-sequencing were conducted on a recently established HBV replication system, through which we identified multiomic differentially expressed genes (DEGs) that HBV orchestrated to remodel host proteostasis networks. Our multiomics interrogation revealed that HBV induced significant changes in both transcription and translation of 35 canonical genes including PPP1R15A, PGAM5 and SIRT6, as well as the expression of at least 15 non-canonical open reading frames (ncORFs) including ncPON2 and ncGRWD1, thus revealing an extra coding potential of human genome. Overexpression of these five genes but not the enzymatically deficient SIRT6 mutants suppressed HBV replication while knockdown of SIRT6 had opposite effect. Furthermore, the expression of SIRT6 was down-regulated in patients, cells or animal models of HBV infection. Mechanistic study further indicated that SIRT6 directly binds to mini-chromosome and deacetylates histone H3 lysine 9 (H3K9ac) and histone H3 lysine 56 (H3K56ac), and chemical activation of endogenous SIRT6 with MDL800 suppressed HBV infection in vitro and in vivo. By generating the first multiomics landscape of host-HBV interaction, our work is thus opening a new avenue to facilitate therapeutic development against HBV infection.

【 授权许可】

CC BY