IFI16 Partners with KAP1 to Maintain Epstein-Barr Virus Latency

Area of Science:

• Virology
• Epigenetics
• Immunology

Background:

• Herpesviruses establish latency for long-term host survival.
• Epstein-Barr virus (EBV) latency requires minimal viral gene expression.
• The host DNA sensor IFI16 facilitates herpesvirus latency via H3K9me3 heterochromatinization.

Purpose of the Study:

• To investigate if IFI16 restricts EBV lytic activation by partnering with the constitutive heterochromatin machinery (HCM).
• To elucidate the mechanism by which IFI16 supports EBV latency.

Main Methods:

• Investigated the interaction between IFI16 and core HCM components (KAP1, SZF1).
• Assessed H3K9 trimethylation at EBV lytic genes.
• Determined the topological relationship of IFI16, KAP1, and SZF1 at the BZLF1 promoter.
• Monitored IFI16 transcription during latency disruption.

Main Results:

• IFI16 physically interacted with KAP1 and SZF1, core components of the HCM.
• This partnership led to the silencing of the EBV lytic switch protein ZEBRA, favoring latency.
• IFI16 contributed to H3K9 trimethylation at EBV lytic genes.
• Disruption of EBV latency correlated with rapid downregulation of IFI16 transcription.

Conclusions:

• IFI16 partners with the HCM to silence EBV lytic genes through heterochromatinization, supporting viral latency.
• This interaction represents a novel antiviral mechanism.
• IFI16 downregulation is critical for the disruption of EBV latency.