AUF1 Is a Novel Negative Regulator for Hepatitis B Virus Replication Acting Through a Posttranscriptional Manner

Elucidating the molecular mechanisms underlying hepatitis B virus (HBV)-host interactions will hold promise for identifying novel therapeutic targets for HBV. This study aims to investigate the functional interplay and regulatory mechanisms between HBV and the AU-rich element RNA-binding protein 1 (AUF1). We demonstrate that AUF1 inhibits HBV replication and expression in HBV-infected HepG2-NTCP cells, HepG2 cells cotransfected with prcccDNA and pCMV-Cre plasmids, and HepAD38 cells. Mechanistically, AUF1 reduces HBV RNA levels post-transcriptionally without altering the transcriptional levels. This suppression occurs primarily through accelerated RNA decay, while translation efficiency remains unaffected. RNA immunoprecipitation confirms AUF1 associates with HBV RNA at multiple binding sites. However, AUF1 and human antigen R (HuR) neither compete for HBV RNA binding nor exhibit antagonistic regulatory functions. Intriguingly, HBV replication significantly reduces intracellular AUF1 protein levels without affecting AUF1 mRNA, suggesting viral induction of AUF1 proteolytic degradation. AUF1 acts as a novel posttranscriptional suppressor of HBV replication via RNA destabilization, revealing a dynamically regulated host-virus conflict where HBV counteracts AUF1 through protein degradation.