Notch signaling facilitates hepatitis B virus covalently closed circular DNA transcription via cAMP response element-binding protein with E3 ubiquitin ligase-modulation.

Abstract:

:Notch1 is regulated by E3 ubiquitin ligases, with proteasomal degradation of the Notch intracellular domain affecting the transcription of target genes. cAMP response element-binding protein (CREB) mediates the transcription of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA). We assessed the relationship between HBV cccDNA and Notch signaling activities. HBV cccDNA levels and relative gene expression were evaluated in HBV-replicating cells treated with Jagged1 shRNA and a γ-secretase inhibitor. The effects of these factors in surgically resected clinical samples were also assessed. Notch inhibition suppressed HBV cccDNA and CREB-related expression but increased ITCH and NUMB levels. Proteasome inhibitor augmented HBV cccDNA, restored Notch and CREB expression, and inhibited ITCH and NUMB function. Increased HBV cccDNA was observed after ITCH and NUMB blockage, even after treatment with the adenylate cyclase activator forskolin; protein kinase A (PKA) inhibitor had the opposite effect. Notch activation and E3 ligase inactivation were observed in HBV-positive cells in clinical liver tissue. Collectively, these findings reveal that Notch signaling activity facilitates HBV cccDNA transcription via CREB to trigger the downstream PKA-phospho-CREB cascade and is regulated by E3 ubiquitin ligase-modulation of the Notch intracellular domain.

journal_name

Sci Rep

journal_title

Scientific reports

authors

Wang Z,Kawaguchi K,Honda M,Hashimoto S,Shirasaki T,Okada H,Orita N,Shimakami T,Yamashita T,Sakai Y,Mizukoshi E,Murakami S,Kaneko S

doi

10.1038/s41598-018-38139-5

subject

Has Abstract

pub_date

2019-02-07 00:00:00

pages

1621

issue

1

issn

2045-2322

pii

10.1038/s41598-018-38139-5

journal_volume

9

pub_type

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