Oncogenic virus hijacks SOX18 pioneer function to enhance viral persistence

Krista Tuohinto; Matthew S. Graus; Peyton Staab; Ville Tiusanen; Fei Liangru; Susav Pradhan; Yew Yan Wong; Simon Weissmann; Jieqiong Lou; Elizabeth Hinde; Justin Wong; Quintin Lee; Alexey V. Terskikh; Martin Alvarez-Kuglen; Tara Karnezis; Thomas Günther; Adam T. Grundhoff; Biswajyoti Sahu; Mathias François; Päivi M. Ojala

doi:10.1101/2025.06.28.662102

Molecular BiologybioRxivJun 28, 2025

Preprint

Oncogenic virus hijacks SOX18 pioneer function to enhance viral persistence

Krista Tuohinto iD, Matthew S. Graus iD, Peyton Staab, Ville Tiusanen iD, Fei Liangru, Susav Pradhan iD, Yew Yan Wong iD, Simon Weissmann, Jieqiong Lou iD, Elizabeth Hinde iD, Justin Wong, Quintin Lee iD, Alexey V. Terskikh iD, Martin Alvarez-Kuglen iD, Tara Karnezis iD, Thomas Günther iD, Adam T. Grundhoff iD, Biswajyoti Sahu iD, Mathias François iD, Päivi M. Ojala iD

Abstract

Kaposis sarcoma herpesvirus (KSHV) establishes lifelong oncogenic infection in lymphatic endothelial cells (LECs) by ensuring episomal maintenance of its genome via the viral protein LANA. Efficient viral genome maintenance typically involves host DNA replication and episome tethering, but the extent of cell-type-specific regulation remains unclear. Here, we identify that KSHV hijacks the pioneering function of the endothelial-specific transcription factor SOX18 to facilitate persistence of viral episomes. Upon infection, LANA co-opts SOX18 to recruit the SWI/SNF chromatin-remodeling complex via its ATPase subunit BRG1, enhancing chromatin accessibility and enabling efficient viral genome persistence. Disruption of SOX18 or BRG1--genetically or pharmacologically--leads to reduced episome load and attenuated hallmarks of virus infection. This work highlights how viruses can harness lineage-specific transcriptional regulators to establish persistent nuclear retention of their episome into the host genome.

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