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Yuan, S.* ; Liao, G.* ; Zhang, M.* ; Zhu, Y.* ; Wang, K.* ; Xiao, W.* ; Jia, C.* ; Dong, M.* ; Sun, N. ; Walch, A.K. ; Xu, P.* ; Zhang, J.* ; Deng, Q.* ; Hu, R.*

Translatomic profiling reveals novel self-restricting virus-host interactions during HBV infection.

J. Hepatol. 75, 74-85 (2021)
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Keywords 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
Quellenangaben Volume: 75, Issue: 1, Pages: 74-85 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Radarweg 29, 1043 Nx Amsterdam, Netherlands
Reviewing status Peer reviewed
Grants 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