Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production

Gramolelli, S.; Elbasani, E.; Nurminen, V.; Tuohinto, K.; Günther, T.; Kallinen, R. E.; Kaijalainen, S. P.; Diaz, R.; Grundhoff, A.; Haglund, C.; Ziegelbauer, J. M.; Bower, M.; Francois, M.; Ojala, P. M.

doi:10.1101/742932

bioRxiv · 10.1101/742932

Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production

Gramolelli, S.·Elbasani, E.·Nurminen, V.·Tuohinto, K.·Günther, T.·Kallinen, R. E.·Kaijalainen, S. P.·Diaz, R.·Grundhoff, A.·Haglund, C.·Ziegelbauer, J. M.·Bower, M.·Francois, M.·Ojala, P. M.

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Abstract

Kaposi sarcoma (KS) is a tumour of endothelial origin caused by KS herpesvirus (KSHV) infection and suggested to originate from lymphatic endothelial cells (LECs). While KSHV establishes latency in virtually all susceptible cell types, LECs support a spontaneous lytic gene expression program with high viral genome copies and release of infectious virus. Here, we investigated the role of PROX1, SOX18 and COUPTF2, drivers of lymphatic endothelial fate during embryogenesis, in this unique KSHV infection program. We found that these factors were co-expressed in KS tumours with the viral lytic marker K8.1, and that SOX18 and PROX1 regulate KSHV infection via two independent mechanisms. SOX18 binds to the viral origins of replication and its depletion or chemical inhibition significantly reduced the KSHV genome copies in LECs. PROX1 interacts with ORF50, the initiator of the lytic cascade, increases lytic gene expression and virus production and its depletion reduces KSHV spontaneous lytic reactivation. Upon lytic replication, PROX1 binds to the KSHV genome in the promoter region of ORF50 and enhances its transactivation activity. These results demonstrate the importance of two endothelial transcription factors in the regulation of the KSHV life cycle and introduce SOX18 inhibition as a potential, novel therapeutic modality for KS.

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Gramolelli, S., Elbasani, E., Nurminen, V., Tuohinto, K., Günther, T., Kallinen, R. E., Kaijalainen, S. P., Diaz, R., Grundhoff, A., Haglund, C., Ziegelbauer, J. M., Bower, M., Francois, M., Ojala, P. M.. 2019-08-27. Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production. https://doi.org/10.1101/742932

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