a capsid-encoded ppxy-motif facilitates adenovirus entry一个capsid-encoded ppxy-motif促进腺病毒条目.pdfVIP

A Capsid-Encoded PPxY-Motif Facilitates Adenovirus Entry Harald Wodrich1,2¤a*, Daniel Henaff1,2, Baptist Jammart1,2¤b, Carolina Segura-Morales1,2¤c, Sigrid 3 4 3 5 1,2 Seelmeir , Olivier Coux , Zsolt Ruzsics , Christopher M. Wiethoff , Eric J. Kremer ´ ´ ´ ´ 1 Institut Genetique Moleculaire de Montpellier, Montpellier, France, 2 Universite Montpellier I II, Montpellier, France, 3 Max von Pettenkofer Institute, Gene Center, LMU ´ Muenchen, Muenchen, Germany, 4 Centre de Recherche en Biochimie Macromoleculaire, Montpellier, France, 5 Department of Microbiology and Immunology, Loyola University Medical Center, Maywood, Illinois, United States of America Abstract 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