Friday, April 26, 2024
4/26/2024
Abstract Human papillomavirus (HPV) is the etiologic agent of cervical cancer, as well as anogenital and oropharyngeal cancers. It is also the most common sexually transmitted infection. Despite the availability of prophylactic vaccines, there are no effective antivirals against active HPV infection. Illuminating the cellular basis of HPV infection is therefore crucial to therapeutic development. Upon receptor-mediated endocytosis, HPV is trafficked to the endosome, the Golgi, and then the nucleus to cause infection. How HPV navigates through this endomembranous network of the host cell remains mysterious. Although recent studies have suggested a role of the host motor dynein in HPV entry, the molecular mechanism by which dynein promotes HPV infection remains unclear. Our preliminary data identified two dynein “cargo adaptors” – the endosome-localized FIP3 and the Golgi-localized BICD2 - as critical host factors during HPV infection. These results suggest that HPV hijacks distinct dynein-cargo adaptor complexes at different entry steps to successfully reach the nucleus. Based on these findings, we hypothesize that the dynein-FIP3 adaptor complex is exploited to transport HPV from the endosome to the Golgi (Aim 1), while the dynein-BICD2 adaptor complex traffics the virus from the Golgi to the nucleus (Aim 2). We will use biochemical, cell-based, and genetic approaches, under loss-of- function conditions, to elucidate the mechanism by which the dynein-adaptor complex drives viral transport. We anticipate that clarifying the role of host components in HPV entry will provide novel strategies to combat HPV-induced diseases.
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