S6K1 inhibits HBV replication through inhibiting AMPK-ULK1 pathway and disrupting acetylation modification of H3K27

Abstract

Aims: To investigated the effect of S6K1 on the replication and transcription of HBV DNA using multiple cell models.

Main methods: The pgRNA, total HBV RNA and HBV DNA level were detected by Real-time PCR. The HBcAg expression by Western blot and the activity of four HBV promoters, such as preS1, preS2/S, core, and X promoters by using dual luciferase reporter assay. Moreover, we determined S6K1 interacted with HBcAg in both cytoplasm and nucleus through Immunofluorescence, co-immunoprecipitation (CoIP) and Western blot.

Key findings: S6K1 inhibited HBV DNA replication and cccDNA-dependent transcription in HBV-expressing stable cell lines. The mechanistic study revealed that S6K1 suppressed HBV DNA replication by inhibiting AMPK-ULK1 autophagy pathway, and the nuclear S6K1 suppressed HBV cccDNA-dependent transcription by inhibiting the acetylation modification of H3K27. In addition, HBV capsid protein (HBcAg) suppressed the phosphorylation level of S6K1Thr389 by interacting with S6K1, indicating a viral antagonism of S6K1-mediated antiviral mechanism.

Significance: The p70 ribosomal S6 kinase (S6K1) is a serine/threonine protein kinase, and it plays a significant role in different cellular processes. It has been previously reported that S6K1 affects hepatitis B virus (HBV) replication but the underlying mechanism remains unclear. In this study, our data suggested that the activation of S6K1 restricts HBV replication through inhibiting AMPK-ULK1 autophagy pathway and H3K27 acetylation. These findings indicated that S6K1 might be a potential therapeutic target for HBV infection.

Keywords: Autophagy; H3K27; HBV inhibition; HBcAg; S6K1.