Topoisomerase IIα orchestrates secretion of IL-6 and IL-8 with human papillomavirus replication.

High-risk human papillomavirus (HPV) replication requires deregulation of host DNA damage response (DDR) and inflammatory pathways. DNA topoisomerase 2β (Top2β) was previously shown to promote HPV replication. We investigated whether its paralog Top2α protein acts similarly to the virus. Elevated levels of Top2α are consistently observed in cervical intraepithelial lesions and the related carcinomas, as well as in HPV-positive cell lines. Silencing Top2α with shRNA severely suppresses HPV genome maintenance and amplification, but in a DDR-independent manner. Instead, Top2α facilitates secretion of interleukin (IL)-6 and IL-8, which are necessary for HPV replication. Mechanistically, this manipulation is regulated by toll-like receptor 4 (TLR4). Top2α binds to the TLR4 promoter to transcriptionally induce TLR4 expression. Blockade of TLR4 signaling by the specific inhibitor TAK-242 significantly reduces the secreted IL-6/IL-8 levels and HPV replication. Overall, our results reveal a novel role of Top2α to shape the inflammatory microenvironment that benefits HPV replication, making it a promising therapeutic target for HPV-associated diseases.