UHRF1 Deficiency Inhibits Alphaherpesvirus through Inducing RIG-I-IRF3-Mediated Interferon Production.

Area of Science:

• Immunology
• Virology
• Epigenetics

Background:

• Type I interferon (IFN-I) response is crucial for innate immunity against viral infections.
• Alphaherpesviruses modulate the IFN-I response to establish persistent infections.
• Understanding epigenetic regulators of IFN-I is vital for antiviral strategies.

Purpose of the Study:

• To investigate the role of DNA methylation regulator UHRF1 in IFN-I induction during alphaherpesvirus infection.
• To elucidate the mechanism by which UHRF1 affects antiviral immunity.
• To evaluate UHRF1 as a potential antiviral target.

Main Methods:

• Knockdown of UHRF1 in cell culture models.
• Assessment of interferon-β (IFN-β) gene transcription and viral inhibition against herpes simplex virus 1 (HSV1) and pseudorabies virus (PRV).
• Analysis of dsRNA accumulation, RIG-I activation, and IRF3 phosphorylation.
• RNase III treatment and double-knockdown assays with DNMT1.

Main Results:

• UHRF1 knockdown significantly enhanced IFN-β-mediated gene transcription and viral inhibition.
• UHRF1 deficiency promoted IFN-I production by activating RIG-I and IRF3 pathways.
• UHRF1 knockdown led to increased double-stranded RNA (dsRNA) accumulation, potentially via DNA demethylation.

Conclusions:

• UHRF1 acts as a potent negative regulator of IFN-I induction during alphaherpesvirus infection.
• UHRF1 plays an essential role in IFN-I-induced antiviral immunity.
• UHRF1 represents a potential therapeutic target for antiviral drug development.