HBV enveloped particle secretion is positively regulated by GRP78 through direct interaction with preS1

Shi, Y.; Jin, X.; Wu, S.; Liu, J.; Zhang, H.; Cai, X.; Yang, Y.; Zhang, X.; wei, J.; Peng, H.; Luo, M.; Zhou, H.; Huang, A.; Wang, D.

doi:10.1101/2021.12.08.471876

bioRxiv · 10.1101/2021.12.08.471876

HBV enveloped particle secretion is positively regulated by GRP78 through direct interaction with preS1

Shi, Y.·Jin, X.·Wu, S.·Liu, J.·Zhang, H.·Cai, X.·Yang, Y.·Zhang, X.·wei, J.·Peng, H.·Luo, M.·Zhou, H.·Huang, A.·Wang, D.

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Abstract

Hepatitis B virus (HBV) infection is a common cause of liver diseases worldwide. Existing drugs do not effectively eliminate HBV from infected hepatocytes; thus, novel curative therapies are needed. Enveloped-particle secretion is a key but poorly studied aspect of the viral life cycle. Here, we report that GRP78 positively regulates HBV enveloped-particle secretion. GRP78 is the specific target of preS1 binding; HBV can upregulate GRP78 in liver cell lines and sera from chronic hepatitis B patients. GRP78 promoted intact HBV-particle secretion in liver cell lines and an HBV transgenic-mouse model. Some peptides screened from preS1 via phage display could inhibit viral-particle secretion by interacting with GRP78 via hydrogen bonds and hydrophobic interactions, thereby disturbing the interaction with HBV particles. These results provide insight into enveloped-particle secretion in the HBV life cycle. GRP78 might be a potential target for HBV-infection treatment via restricting GRP78-preS1 interactions to block viral-particle secretion. IMPORTANCEHBV is a major human pathogen. The virus More than 250 million n individuals globally are chronically infected with HBV and can result in the infected personsabout 800,000 die for HBV-related disease annually. The mature HBV enveloped particles containing HBs and the relaxed circular (RC) DNA genome could secreted extracellularly as virions. And these enveloped virions serves as the infectious HBV particles for initiating a complete life cycle of the virus. Here, we show the GRP78 is the specific target of preS1 binding, and it could positive regulate HBV enveloped particle secretion in cell and HBV transgenic mice model. Furthermore, several peptides screened from preS1 and Phage screening could inhibit viral particle secretion by interacting with GRP78 and disturbing its interaction with HBV, and then block the life cycle of the virus. This has important implications for our understanding of the mechanisms of antivirals that target intact HBV particles secretion.

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Shi, Y., Jin, X., Wu, S., Liu, J., Zhang, H., Cai, X., Yang, Y., Zhang, X., wei, J., Peng, H., Luo, M., Zhou, H., Huang, A., Wang, D.. 2021-12-10. HBV enveloped particle secretion is positively regulated by GRP78 through direct interaction with preS1. https://doi.org/10.1101/2021.12.08.471876

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