Hepatitis B virus hijacks TSG101 to facilitate egress via multiple vesicle bodies

Hepatitis B virus (HBV) chronically infects 296 million individuals and there is no cure. As an important step of viral life cycle, the mechanisms of HBV egress remain poorly elucidated. With proteomic approach to identify capsid protein (HBc) associated host factors and siRNA screen, we uncovered t...

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Bibliographic Details
Published in:PLoS pathogens 2023-05, Vol.19 (5), p.e1011382-e1011382
Main Authors: Zheng, Yingcheng, Wang, Mengfei, Li, Sitong, Bu, Yanan, Xu, Zaichao, Zhu, Guoguo, Wu, Chuanjian, Zhao, Kaitao, Li, Aixin, Chen, Quan, Wang, Jingjing, Hua, Rong, Teng, Yan, Zhao, Li, Cheng, Xiaoming, Xia, Yuchen
Format: Article
Language:English
Subjects:
Animals
Antibodies
Antigens
Autophagy
Biology and Life Sciences
Capsid protein
Cell culture
Complications and side effects
Development and progression
DNA-Binding Proteins - genetics
Egress
Genetic aspects
Genetic screening
Genomes
Heparan sulfate
Hepatitis
Hepatitis B
Hepatitis B virus
Hepatitis B virus - genetics
Host-virus relationships
Immunoprecipitation
Infections
Life cycles
Mass spectrometry
Medicine and health sciences
Mice
Mice, Transgenic
Mutagenesis
Physiological aspects
Proteins
Proteomics
Research and Analysis Methods
Scientific imaging
siRNA
Transcription Factors - genetics
Transgenic animals
Transgenic mice
Transmission electron microscopy
Ubiquitin
Ubiquitin-conjugating enzyme
Ubiquitin-protein ligase
Ubiquitination
Viral proteins
Viruses
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Summary:Hepatitis B virus (HBV) chronically infects 296 million individuals and there is no cure. As an important step of viral life cycle, the mechanisms of HBV egress remain poorly elucidated. With proteomic approach to identify capsid protein (HBc) associated host factors and siRNA screen, we uncovered tumor susceptibility gene 101 (TSG101). Knockdown of TSG101 in HBV-producing cells, HBV-infected cells and HBV transgenic mice suppressed HBV release. Co-immunoprecipitation and site mutagenesis revealed that VFND motif in TSG101 and Lys-96 ubiquitination in HBc were essential for TSG101-HBc interaction. In vitro ubiquitination experiment demonstrated that UbcH6 and NEDD4 were potential E2 ubiquitin-conjugating enzyme and E3 ligase that catalyzed HBc ubiquitination, respectively. PPAY motif in HBc and Cys-867 in NEDD4 were required for HBc ubiquitination, TSG101-HBc interaction and HBV egress. Transmission electron microscopy confirmed that TSG101 or NEDD4 knockdown reduces HBV particles count in multivesicular bodies (MVBs). Our work indicates that TSG101 recognition for NEDD4 ubiquitylated HBc is critical for MVBs mediated HBV egress.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1011382