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

  • Life Sci. 2021 Jan 15;265:118848. doi: 10.1016/j.lfs.2020.118848.
Yun Wang  1 ,  Ming Han  2 ,  Shunai Liu  2 ,  Xiaoxue Yuan  2 ,  Jing Zhao  3 ,  Hongping Lu  4 ,  Kai Han  2 ,  Pu Liang  2 ,  Jun Cheng  5
Affiliations
  • 1. Peking University Ditan Teaching Hospital, Beijing 100015, China; Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China.
  • 2. Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China.
  • 3. Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China; Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, Henan, China.
  • 4. Beijing Pan-Asia Tongze Institute of Biomedicine Co, Ltd, Beijing 100103, China.
  • 5. Peking University Ditan Teaching Hospital, Beijing 100015, China; Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China; Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, Beijing 100191, China. Electronic address: [email protected].
PMID: 33278383 DOI: 10.1016/j.lfs.2020.118848
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.
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