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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Translatomic profiling reveals novel self-restricting virus-host interactions during HBV infection.
J. Hepatol. 75, 74-85 (2021)
BACKGROUND AND AIMS: Hepatitis B Virus remains to be yet unresolved global threat to human health. It remains incompletely understood how HBV self-restricts in host during most adulthood infections, and multi-omics analyses were performed to systematically interrogate into HBV-host interaction and the life cycle of HBV. METHODS: RNA-sequencing and ribosome profiling were conducted with cell-based models for HBV replication and gene expression. The novel translational events or products hereby detected were then characterized, and functionally assessed in both cell and mouse models. Moreover, quasi-species analyses of HBV subpopulations were conducted with patients at immune tolerance or activation phases, using next- or third-generation sequencing. RESULTS: We identified EnhI-SL (Enhancer I-stem loop) as a new cis element in HBV genome, and the mutations disrupting EnhI-SL were found to elevate viral polymerase expression. Furthermore, while re-discovering HpZ/P', a previously under-explored isoform of HBV polymerase, we also identified HBxZ as a novel short isoform of HBX and confirmed their existence and functionally characterized them as potent suppressors for HBV gene expression or genome replication. Mechanistically, HpZ/P' was found to repress HBV gene expression partially through interacting with, and sequestering SUPV3L1. The abundances of the HBV mutants either deficient of HpZ/P' or disrupted in EnhI-SL seemed to be diminished upon the activation of host immune system. Finally, SRSF2, a HBV-down-regulated host protein in RNA spliceosome, was found to promote the splicing of viral pre-genomic RNA and HpZ/P' biogenesis. CONCLUSION: This study has identified multiple viral self-restricting mechanisms in HBV-host interaction. Particularly, SRSF2-HpZ/P' appeared to constitute another negative feedback mechanism in controlling HBV life-cycle. Targeting host splicing machinery might thus represent a yet under-explored strategy to intervene into HBV-host interaction.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Enhi-sl ; Hbv ; Hbxz ; Hpz/p’ ; Ribosome-profiling ; Translatomic; Hepatitis-b-virus; Viral Persistence; Spliced Rna; In-vivo; Identification; Protein; Dna
ISSN (print) / ISBN
0168-8278
e-ISSN
1600-0641
Zeitschrift
Journal of Hepatology
Quellenangaben
Band: 75,
Heft: 1,
Seiten: 74-85
Verlag
Elsevier
Verlagsort
Radarweg 29, 1043 Nx Amsterdam, Netherlands
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Research Unit Analytical Pathology (AAP)
Förderungen
Shenzhen-Hong Kong Institute of Brain Science
National Natural Science Foundation of China
Strategic Priority Research Program of the Chinese Academy of Sciences
National Key R&D Program of China
Youth Innovation Promotion Association of the Chinese Academy of Sciences
Department of Science and Technology of Zhejiang Province
National Science and Technology Major Project
National Natural Science Foundation of China
Strategic Priority Research Program of the Chinese Academy of Sciences
National Key R&D Program of China
Youth Innovation Promotion Association of the Chinese Academy of Sciences
Department of Science and Technology of Zhejiang Province
National Science and Technology Major Project