p120 catenin recruits HPV to γ-secretase to promote virus infection

Author summary Human papillomavirus (HPV) is the primary cause of cervical, anogenital, and oropharyngeal cancers. Despite the significant impact of HPV on human health, there is limited understanding of how this small DNA virus traffics through a host cell to cause infection. This work identifies the role of the cellular factor p120 catenin in routing the virus along a productive entry pathway. Specifically, we propose that p120 targets HPV to the transmembrane protein gamma-secretase, a critical step of viral entry. This work thus provides insights into the intracellular transport mechanisms of HPV and identifies a potential therapeutic target for HPV treatment. During internalization and trafficking, human papillomavirus (HPV) moves from the cell surface to the endosome where the transmembrane protease gamma-secretase promotes insertion of the viral L2 capsid protein into the endosome membrane. Protrusion of L2 through the endosome membrane into the cytosol allows the recruitment of cytosolic host factors that target the virus to the Golgien routefor productive infection. How endosome-localized HPV is delivered to gamma-secretase, a decisive infection step, is unclear. Here we demonstrate that cytosolic p120 catenin, likely via an unidentified transmembrane protein, interacts with HPV at early time-points during viral internalization and trafficking. In the endosome, p120 is not required for low pH-dependent disassembly of the HPV L1 capsid protein from the incoming virion. Rather, p120 is required for HPV to interact with gamma-secretase-an interaction that ensures the virus is transported along a productive route. Our findings clarify an enigmatic HPV infection step and provide critical insights into HPV infection that may lead to new therapeutic strategies against HPV-induced diseases.