Oncogenic virus hijacks SOX18 pioneer function to enhance viral persistence

Area of Science:

• Virology
• Molecular Biology
• Oncology

Background:

• Kaposi's sarcoma herpesvirus (KSHV) establishes lifelong infections, primarily in lymphatic endothelial cells (LECs).
• Viral episomal genome maintenance is crucial for persistent KSHV infection, involving host DNA replication and tethering.
• The specific regulatory mechanisms of viral genome maintenance in a cell-type-specific manner are not fully understood.

Purpose of the Study:

• To investigate how KSHV ensures the persistence of its episomal genome within host cells.
• To identify the role of cell-type-specific factors in KSHV episome maintenance.
• To elucidate the molecular mechanisms by which KSHV interacts with host cellular machinery.

Main Methods:

• Investigated the interaction between KSHV's LANA protein and host cellular factors.
• Utilized genetic and pharmacological disruption of SOX18 and BRG1.
• Assessed viral episome load and hallmarks of KSHV infection.

Main Results:

• KSHV hijacks the endothelial-specific transcription factor SOX18 for viral episome persistence.
• LANA recruits the SWI/SNF chromatin-remodeling complex, specifically BRG1, through SOX18.
• Disruption of SOX18 or BRG1 significantly reduces viral episome load and infection hallmarks.

Conclusions:

• KSHV exploits SOX18's pioneering function in LECs to maintain its episomal genome.
• The LANA-SOX18-BRG1 axis is critical for efficient viral genome persistence and chromatin accessibility.
• Viruses can leverage lineage-specific transcriptional regulators to establish persistent nuclear episome retention.