Abstract
The hepatitis B virus (HBV) core protein (HBc) functions in multiple steps of the viral life cycle. Heteroaryldihydropyrimidine compounds (HAPs) such as Bay41-4109 are capsid protein allosteric modulators that accelerate HBc degradation and inhibit the virion secretion of HBV, specifically by misleading HBc assembly into aberrant non-capsid polymers. However, the subsequent cellular fates of these HAP-induced aberrant non-capsid polymers are not well understood. Here, we discovered that that the chaperone-binding E3 ubiquitin ligase protein STUB1 is required for the removal of Bay41-4109-induced aberrant non-capsid polymers from HepAD38 cells. Specifically, STUB1 recruits BAG3 to transport Bay41-4109-induced aberrant non-capsid polymers to the perinuclear region of cells, thereby initiating p62-mediated macroautophagy and lysosomal degradation. We also demonstrate that elevating the STUB1 level enhances the inhibitory effect of Bay41-4109 on the production of HBeAg and HBV virions in HepAD38 cells, in HBV-infected HepG2-NTCP cells, and in HBV transgenic mice. STUB1 overexpression also facilitates the inhibition of Bay41-4109 on the cccDNA formation in de novo infection of HBV. Understanding these molecular details paves the way for applying HAPs as a potentially curative regimen (or a component of a combination treatment) for eradicating HBV from hepatocytes of chronic infection patients.
Highlights
Chronic hepatitis B virus (HBV) infection results in a significantly elevated risk of developing liver cirrhosis and hepatocellular carcinoma [1]
This study aimed to investigate how a Heteroaryldihydropyrimidine compounds (HAPs) compound Bay41-4109 induces the degradation of HBV core protein (HBc) protein
We found that the chaperone-binding E3 ligase STIP1 Homology And U Box-Containing Protein 1 (STUB1) drives Bay41-4109-induced HBc degradation via the macroautophagy-lysosome pathway and that elevation of the STUB1 level enhances the inhibitory effect of Bay41-4109 on the production of both HBeAg and HBV virions
Summary
Chronic hepatitis B virus (HBV) infection results in a significantly elevated risk of developing liver cirrhosis and hepatocellular carcinoma [1]. The HBV core protein (HBc) is the structural component of the nucleocapsid packaging of the viral genome and DNA polymerase [4]. HBc is viewed as a promising target for antiviral drug development because it participates in multiple steps of the viral life cycle, including RNA packaging, DNA synthesis, viral maturation, and recognition of viral envelope proteins [5]. Drugs known as capsid protein allosteric modulators (CpAMs) have been developed to target HBc. CpAMs can be classified into two types according to their mode of action [6]. Given that HAP may induce aberrant polymers of intracellular HBe, treatment with HAPs disrupts the capacity for HBeAg production [17,19]. Several HAPs are currently undergoing clinical trials, the molecular basis for the degradation of HAP-induced aberrant non-capsid polymers remains unclear
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