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

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.

HPV16 Entry into Epithelial Cells: Running a Gauntlet

“…The relevance of the transmembrane protease γ-secretase for the HPV entry process is well-documented [99,[103][104][105][106][107][108]. Here, a novel chaperone-like function of the γ-secretase seems to be more important than its role as a protease, as it enables low pH-dependent membrane insertion of the furin-cleaved L2 that is required for further trafficking [25,[104][105][106].…”

How DNA and RNA Viruses Exploit Host Chaperones to Promote Infection

“…The delivery of HPV to γ-secretase in the endosome relies on the cytosolic γ-secretase adaptor p120 catenin, which normally targets cellular transmembrane proteins to γ-secretase [ 61 , 62 , 63 ]. In this scenario, HPV is thought to be delivered to γ-secretase when p120 targets an unidentified transmembrane protein—which is in complex with HPV—to γ-secretase.…”

“…In this scenario, HPV is thought to be delivered to γ-secretase when p120 targets an unidentified transmembrane protein—which is in complex with HPV—to γ-secretase. Not surprisingly, the mutation of γ-secretase that disrupts γ-secretase-p120 binding prevents HPV infection [ 61 ]. Thus, HPV co-opts host soluble and transmembrane chaperones that facilitate viral internalization, disassembly, and endosomal membrane insertion to cause infection.…”

Recent Advances in Our Understanding of the Infectious Entry Pathway of Human Papillomavirus Type 16

“…The connection between y-secretase and infectious HPV entry has been further elaborated on since our last review. First, the protein p120 is required for HPV to engage with ysecretase [92]. p120 has previously been shown to recruit cadherins to the y-secretase complex via PS1 binding to p120 [93].…”