A capsid-encoded PPxY-motif facilitates adenovirus entry.

Viruses use cellular machinery to enter and infect cells. In this
study we address the cell entry mechanisms of nonenveloped
adenoviruses (Ads). We show that protein VI, an internal capsid
protein, is rapidly exposed after cell surface attachment and
internalization and remains partially associated with the capsid
during intracellular transport. We found that a PPxY motif within
protein VI recruits Nedd4 E3 ubiquitin ligases to bind and
ubiquitylate protein VI. We further show that this PPxY motif is
involved in rapid, microtubule-dependent intracellular movement of
protein VI. Ads with a mutated PPxY motif can efficiently escape
endosomes but are defective in microtubule-dependent trafficking
toward the nucleus. Likewise, depletion of Nedd4 ligases attenuates
nuclear accumulation of incoming Ad particles and infection. Our
data provide the first evidence that virus-encoded PPxY motifs are
required during virus entry, which may be of significance for
several other pathogens.