Abstract
The Endosomal Sorting Complex Required for Transport (ESCRT) is an important cellular machinery for the sorting and trafficking of ubiquitinated cargos. It is also known that ESCRT is required for the egress of a number of viruses. To investigate the relationship between ESCRT and hepatitis B virus (HBV), we conducted an siRNA screening of ESCRT components for their potential effect on HBV replication and virion release. We identified a number of ESCRT factors required for HBV replication, and focused our study here on HGS (HRS, hepatocyte growth factor-regulated tyrosine kinase substrate) in the ESCRT-0 complex. Aberrant levels of HGS suppressed HBV transcription, replication and virion secretion. Hydrodynamic delivery of HGS in a mouse model significantly suppressed viral replication in the liver and virion secretion in the serum. Surprisingly, overexpression of HGS stimulated the release of HBV naked capsids, irrespective of their viral RNA, DNA, or empty contents. Mutant core protein (HBc 1–147) containing no arginine-rich domain (ARD) failed to secrete empty virions with or without HGS. In contrast, empty naked capsids of HBc 1–147 could still be promoted for secretion by HGS. HGS exerted a strong positive effect on the secretion of naked capsids, at the expense of a reduced level of virions. The association between HGS and HBc appears to be ubiquitin-independent. Furthermore, HBc is preferentially co-localized with HGS near the cell periphery, instead of near the punctate endosomes in the cytoplasm. In summary, our work demonstrated the importance of an optimum level of HGS in HBV propagation. In addition to an effect on HBV transcription, HGS can diminish the pool size of intracellular nucleocapsids with ongoing genome maturation, probably in part by promoting the secretion of naked capsids. The secretion routes of HBV virions and naked capsids can be clearly distinguished based on the pleiotropic effect of HGS involved in the ESCRT-0 complex.
Highlights
Hepatitis B virus is a leading cause of chronic liver diseases and more than 240 million people are infected worldwide
We identified many host factors known to be involved in a membrane trafficking machinery, as well as required for hepatitis B virus (HBV) replication
We entertain the possibility that HGS and other Endosomal Sorting Complex Required for Transport (ESCRT) factors may be further developed into a therapeutic treatment for hepatitis B
Summary
Hepatitis B virus is a leading cause of chronic liver diseases and more than 240 million people are infected worldwide. One of the best-known functions of ESCRT is its role in targeting ubiquitinated cargos of recycled host factors into vacuoles, such as multivesicular bodies (MVBs) [5] This ESCRT machinery can be divided into five components known as ESCRT-0, -I, -II, -III and VPS4 ATPase complex. The lateacting ESCRT-III is able to catalyse the scission of membrane necks, which can support the formation of intraluminal vesicles [10,11] These sequentially formatted ESCRT complexes will be disassembled by VPS4-mediated ATPase activity and recycled back to the cytoplasm [12]. While ESCRT-I seemed to have no significant effect on HBV production, ESCRT-II and -III appeared to be involved in viral maturation and egress [18,19] To date, it remains to be elucidated whether ESCRT-0 has a role in HBV life cycle
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