Steroid receptor coactivator 3 inhibits hepatitis B virus gene expression through activating Akt signaling to prevent HNF4α nuclear translocation

Li, Ming; Wang, Yi; Xia, Xiaochun; Mo, Pingli; Xu, Jianming; Yu, Chundong; Li, Wengang

doi:10.1186/s13578-019-0328-5

Cited by 5 publications

(6 citation statements)

References 24 publications

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“…The PI3K/AKT signaling pathway plays an important role in regulating the transcriptional activities of SP1 and HNF4α ( Adapala et al, 2019 ; Gómez-Villafuertes et al, 2015 ; Li et al, 2019 ; Zhao et al, 2015 ). Activation of AKT promotes the stability and localization of SP1 by phosphorylating SP1 at Thr453 and Thr739 ( Adapala et al, 2019 ; Gómez-Villafuertes et al, 2015 ; Zhao et al, 2015 ), and prevents the nuclear translocation of HNF4α ( Li et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

Transcriptional regulation of SARS-CoV-2 receptor ACE2 by SP1

Han,

Luo,

Long

et al. 2024

eLife

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Angiotensin-converting enzyme 2 (ACE2) is a major cell entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The induction of ACE2 expression may serve as a strategy by SARS-CoV-2 to facilitate its propagation. However, the regulatory mechanisms of ACE2 expression after viral infection remain largely unknown. Using 45 different luciferase reporters, the transcription factors SP1 and HNF4α were found to positively and negatively regulate ACE2 expression, respectively, at the transcriptional level in human lung epithelial cells (HPAEpiCs). SARS-CoV-2 infection increased the transcriptional activity of SP1 while inhibiting that of HNF4α. The PI3K/AKT signaling pathway, activated by SARS-CoV-2 infection, served as a crucial regulatory node, inducing ACE2 expression by enhancing SP1 phosphorylation—a marker of its activity—and reducing the nuclear localization of HNF4α. However, colchicine treatment inhibited the PI3K/AKT signaling pathway, thereby suppressing ACE2 expression. In Syrian hamsters (Mesocricetus auratus) infected with SARS-CoV-2, inhibition of SP1 by either mithramycin A or colchicine resulted in reduced viral replication and tissue injury. In summary, our study uncovers a novel function of SP1 in the regulation of ACE2 expression and identifies SP1 as a potential target to reduce SARS-CoV-2 infection.

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Section: Resultsmentioning

confidence: 99%

Transcriptional regulation of SARS-CoV-2 receptor ACE2 by SP1

Han,

Luo,

Long

et al. 2024

eLife

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Section: Resultsmentioning

confidence: 99%

“…The PI3K/AKT signaling pathway plays an important role in regulating the transcriptional activity of Sp1 and HNF4α (Adapala et al, 2019, Gomez-Villafuertes et al, 2015, Zhao et al, 2015, Li et al, 2019). Activation of AKT promotes the stability and localization of Sp1 by phosphorylating Sp1 at threonine sites 453 and 739 (Adapala et al, 2019, Gomez-Villafuertes et al, 2015, Zhao et al, 2015), and prevents the nuclear translocation of HNF4α (Li et al, 2019). Consistent with these observations, we found that suppression of AKT by siRNA or its inhibitors significantly inhibited the accumulation of phospho-Sp1 in the nucleus, but remarkably promoted nuclear translocation of HNF4α (Figure 5H-5K).…”

Section: Resultsmentioning

confidence: 99%

Transcription regulation of SARS-CoV-2 receptor ACE2 by Sp1: a potential therapeutic target

Han

Luo

Long

et al. 2023

Preprint

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Angiotensin-converting enzyme 2 (ACE2) is a major cell entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Induction of ACE2 expression may represent an effective tactic employed by SARS-CoV-2 to facilitate its own propagation. However, the regulatory mechanisms of ACE2 expression after viral infection remain largely unknown. By employing an array of 45 different luciferase reporters, we identify that the transcription factor Sp1 positively and HNF4α negatively regulate the expression of ACE2 at the transcriptional levels in HPAEpiC cells, a human lung epithelial cell line. SARS-CoV-2 infection promotes and inhibits the transcription activity of Sp1 and HNF4α, respectively. The PI3K/AKT signaling pathway, which is activated by SARS-CoV-2 infection, is a crucial node for induction of ACE2 expression by increasing Sp1 phosphorylation, an indicator of its activity, and reducing HNF4α nuclear location. Furthermore, we show that colchicine could inhibit the PI3K/AKT signaling pathway, thereby suppressing ACE2 expression. Inhibition of Sp1 by either its inhibitor mithramycin A or colchicine reduces viral replication and tissue injury in Syrian hamsters infected with SARS-CoV-2. In summary, our study uncovers a novel function of Sp1 in regulating ACE2 expression and suggests that Sp1 is a potential target to reduce SARS-CoV-2 infection.

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“…Consequently, the interactions between CRY and glucocorticoid receptors affect carbohydrate metabolism, hence transacting PER2 [ 87 ]. HNF4α increases the transcription of pgRNA in hepatoma cells and thus affects HBV biosynthesis[ 88 ]. In addition, P2-HNF4α inhibits the expression of BMAL1 , leading to the localization of P1-HNF4α from the nucleus to the cytoplasm.…”

Section: Circadian Rhythmmentioning

confidence: 99%

Hepatitis B and circadian rhythm of the liver

Škrlec¹,

Talapko²

2022

WJG

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The circadian rhythm in humans is determined by the central clock located in the hypothalamus’s suprachiasmatic nucleus, and it synchronizes the peripheral clocks in other tissues. Circadian clock genes and clock-controlled genes exist in almost all cell types. They have an essential role in many physiological processes, including lipid metabolism in the liver, regulation of the immune system, and the severity of infections. In addition, circadian rhythm genes can stimulate the immune response of host cells to virus infection. Hepatitis B virus (HBV) infection is the leading cause of liver disease and liver cancer globally. HBV infection depends on the host cell, and hepatocyte circadian rhythm genes are associated with HBV replication, survival, and spread. The core circadian rhythm proteins, REV-ERB and brain and muscle ARNTL-like protein 1, have a crucial role in HBV replication in hepatocytes. In addition to influencing the virus’s life cycle, the circadian rhythm also affects the pharmacokinetics and efficacy of antiviral vaccines. Therefore, it is vital to apply antiviral therapy at the appropriate time of day to reduce toxicity and improve the effectiveness of antiviral treatment. For these reasons, understanding the role of the circadian rhythm in the regulation of HBV infection and host responses to the virus provides us with a new perspective of the interplay of the circadian rhythm and anti-HBV therapy. Therefore, this review emphasizes the importance of the circadian rhythm in HBV infection and the optimization of antiviral treatment based on the circadian rhythm-dependent immune response.

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Steroid receptor coactivator 3 inhibits hepatitis B virus gene expression through activating Akt signaling to prevent HNF4α nuclear translocation

Cited by 5 publications

References 24 publications

Transcriptional regulation of SARS-CoV-2 receptor ACE2 by SP1

Transcriptional regulation of SARS-CoV-2 receptor ACE2 by SP1

Transcription regulation of SARS-CoV-2 receptor ACE2 by Sp1: a potential therapeutic target

Hepatitis B and circadian rhythm of the liver

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