SPOP inhibits HBV transcription and replication by ubiquitination and degradation of HNF1α

Yubo Pi, Yang Li, Qi Yan, Huimin Luo, Peng Zhou, Wenyi Chang, Deao Gong, Yuan Hu, Kai Wang, Ni Tang, 

Ailong Huang, Yanmeng Chen

Abstract

Hepatitis B virus (HBV) infection remains a significant public health burden worldwide. The persistence of covalently closed circular DNA (cccDNA) within the nucleus of infected hepatocytes is responsible for the failure of antiviral treatments. The ubiquitin proteasome system (UPS) has emerged as a promising antiviral target, as it can regulate HBV replication by promoting critical protein degradation in steps of viral life cycle. Speckle-type POZ protein (SPOP) is a critical adaptor for Cul3-RBX1 E3 ubiquitin ligase complex, but the effect of SPOP on HBV replication is less known. Here, we identified SPOP as a novel host antiviral factor against HBV infection. SPOP overexpression significantly inhibited the transcriptional activity of HBV cccDNA without affecting cccDNA level in HBV-infected HepG2-NTCP and primary human hepatocyte cells. Mechanism studies showed that SPOP interacted with hepatocyte nuclear factor 1α (HNF1α), and induced HNF1α degradation through host UPS pathway. Moreover, the antiviral role of SPOP was also confirmed in vivo. Together, our findings reveal that SPOP is a novel host factor which inhibits HBV transcription and replication by ubiquitination and degradation of HNF1α, providing a potential therapeutic strategy for the treatment of HBV infection.

DOI: 10.1002/jmv.29254

A model of the mechanism by which SPOP inhibits HBV transcription. 

SPOP serves as an antiviral factor that interacts with transcriptional activator HNF1α and induces HNF1α ubiquitination and degradation via UPS pathway, which impairs the ability of HNF1α to transcriptionally activate HBV cccDNA. 

Full text: https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.29254