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.

The PPxY motif in protein VI seems to favor interaction with Nedd4.1 and Nedd4.2 although we observed interactions with AIP4/Itch and WWP1 as well. It is possible that an interaction between protein VI and WWP1, as we observe in transient transfections, is circumvented by exposure of the PPxY domain after the virus has entered the endosomal compartment. A role for Nedd4.1 or Nedd4.2 in Ad entry is underscored by our observation that Nedd4.2 can directly ubiquitylate protein VI via the PPxY motif and its depletion (and to a lesser extent also depletion of Nedd4.1) reduces Ad transduction. In addition this depletion also reduced MTOC accumulation of viral particles following infection, which is similar to the effect of the PPxY mutation in the M1 virus. However the effects were modest, indicating that additional mechanisms contribute to Ad entry. Further studies will be needed to identify a specific role for each ligase in Ad entry and trafficking towards the MTOC and to determine whether other ligases like AIP4/Itch and WWP1 are involved.