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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 Discov. 7:105 (2021)
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.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Hepatitis-b-virus; Closed Circular Dna; Histone Deacetylase Sirt6; X Protein; In-vivo; Epigenetic Regulation; Viral Persistence; Cell-culture; Amino-acids; Translation
ISSN (print) / ISBN
2056-5968
e-ISSN
2056-5968
Zeitschrift
Cell Discovery
Quellenangaben
Band: 7,
Heft: 1,
Artikelnummer: 105
Verlag
Springer
Verlagsort
Campus, 4 Crinan St, London, N1 9xw, England
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Research Unit Analytical Pathology (AAP)
Förderungen
Youth Innovation Promotion Association of the Chinese Academy of Sciences
National Key R&D Program of China
Shanghai Municipal Science and Technology Major Project
Strategic Priority Research Program of the Chinese Academy of Sciences
National Science and Technology Major Project
Department of Science and Technology of Zhejiang Province
Shenzhen Hong Kong Institute of Brain Science
China Postdoctoral Science Foundation
National Natural Science Foundation of China
National Key R&D Program of China
Shanghai Municipal Science and Technology Major Project
Strategic Priority Research Program of the Chinese Academy of Sciences
National Science and Technology Major Project
Department of Science and Technology of Zhejiang Province
Shenzhen Hong Kong Institute of Brain Science
China Postdoctoral Science Foundation
National Natural Science Foundation of China