A Capsid-Encoded PPxY-Motif Facilitates Adenovirus Entry

Wodrich, Harald; Henaff, Daniel; Jammart, Baptist; Segura-Morales, Carolina; Seelmeir, Sigrid; Coux, Olivier; Ruzsics, Zsolt; Wiethoff, Christopher M.; Kremer, Eric J.

In this study we show that the Ads internal capsid protein VI harbors a PPxY-motif that is involved in virus entry and infectivity. For Ads, reaching the nucleus requires a series of sequential steps: receptor-mediated endocytic uptake, partial capsid disassembly, endosomal rupture, microtubule based transport to the MTOC and nuclear trafficking. The link between these steps has been best exemplified in the case of the thermostable temperature-sensitive mutant Ad2ts1. This mutant enters cells by receptor-mediated endocytosis, but remains in an endosomal compartment due to increased capsid stability. Therefore, Ad2ts1 particles are directed to lysosomes for destruction and/or recycled back to the surface thus precluding accumulation at the nuclear pore complex [26, 28, 39] . The role of facilitating endosomal escape during Ad entry was initially assigned to the penton base [40] . Later, Wiethoff and co-workers showed that most membrane lytic activity of Ad viral capsids comes from the predicted N-terminal amphipathic helix of the internal capsid protein VI, and that membrane lytic activity required partial capsid disassembly to release protein VI [28] .