P120 catenin recruits HPV to γ-secretase to promote virus infection.

Mara Calypso Harwood,Daniel Dimaio,Takamasa Inoue,Allison Jade Dupzyk,Billy Tsai,Richard Bs Roden

doi:10.1371/journal.ppat.1008946

Mara Calypso Harwood, Daniel Dimaio + Show 4 more

Open Access

https://doi.org/10.1371/journal.ppat.1008946

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Abstract

During internalization and trafficking, human papillomavirus (HPV) moves from the cell surface to the endosome where the transmembrane protease γ-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 Golgi en route for productive infection. How endosome-localized HPV is delivered to γ-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 γ-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.

Highlights

Human papillomavirus (HPV) infects nearly 80 million U.S adults [1] and is the primary cause of cervical, anogenital, and oropharyngeal cancers [2]
This work identifies the role of the cellular factor p120 catenin in routing the virus along a productive entry pathway
We report here that HPV interacts with cytosolic p120, likely via a transmembrane receptor, at the cell surface

Summary

Introduction

Human papillomavirus (HPV) infects nearly 80 million U.S adults [1] and is the primary cause of cervical, anogenital, and oropharyngeal cancers [2]. While efficacious prophylactic vaccines exist against 7 of the cancer-causing HPVs [2], the vaccines have not been efficiently utilized, with over half the target population remaining unvaccinated in the U.S [3]. Identifying host factors essential for HPV infection may reveal novel targets for anti-viral therapy and remains an important objective in combating HPV-induced diseases. HPV is a nonenveloped virus composed of the viral capsid proteins L1 and L2 which encase the viral DNA genome [5]. After endocytosis, HPV is delivered to the endosome, where some of the L1 and L2 molecules are disassembled from the incoming virus particle [22,23]

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