title: Multi-layered control of Galectin-8 mediated autophagy during adenovirus cell entry through a conserved PPxY motif in the viral capsid.
abstract: Cells employ active measures to restrict infection by pathogens, even prior to responses from the innate and humoral immune defenses. In this context selective autophagy is activated upon pathogen induced membrane rupture to sequester and deliver membrane fragments and their pathogen contents for lysosomal degradation. Adenoviruses, which breach the endosome upon entry, escape this fate by penetrating into the cytosol prior to autophagosome sequestration of the ruptured endosome. We show that virus induced membrane damage is recognized through Galectin-8 and sequesters the autophagy receptors NDP52 and p62. We further show that a conserved PPxY motif in the viral membrane lytic protein VI is critical for efficient viral evasion of autophagic sequestration after endosomal lysis. Comparing the wildtype with a PPxY-mutant virus we show that depletion of Galectin-8 or suppression of autophagy in ATG5-/- MEFs rescues infectivity of the PPxY-mutant virus while depletion of the autophagy receptors NDP52, p62 has only minor effects. Furthermore we show that wildtype viruses exploit the autophagic machinery for efficient nuclear genome delivery and control autophagosome formation via the cellular ubiquitin ligase Nedd4.2 resulting in reduced antigenic presentation. Our data thus demonstrate that a short PPxY-peptide motif in the adenoviral capsid permits multi-layered viral control of autophagic processes during entry.
authors.affiliation: MFP CNRS UMR 5234, Microbiologie Fondamentale et Pathogénicité, Université de Bordeaux, Bordeaux, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Montespan
authors.affiliation: Department of Microbiology and Immunology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, United States of America.
authors.forename: Shauna A
authors.initials: SA
authors.lastname: Marvin
authors.affiliation: MFP CNRS UMR 5234, Microbiologie Fondamentale et Pathogénicité, Université de Bordeaux, Bordeaux, France.
authors.forename: Sisley
authors.identifier: 0000-0001-8348-3041
authors.initials: S
authors.lastname: Austin
authors.affiliation: Department of Microbiology and Immunology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, United States of America.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Burrage
authors.affiliation: MFP CNRS UMR 5234, Microbiologie Fondamentale et Pathogénicité, Université de Bordeaux, Bordeaux, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Roger
authors.affiliation: MFP CNRS UMR 5234, Microbiologie Fondamentale et Pathogénicité, Université de Bordeaux, Bordeaux, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Rayne
authors.affiliation: MFP CNRS UMR 5234, Microbiologie Fondamentale et Pathogénicité, Université de Bordeaux, Bordeaux, France.
authors.forename: Muriel
authors.identifier: 0000-0002-2013-5776
authors.initials: M
authors.lastname: Faure
authors.affiliation: Department of Microbiology and Immunology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, United States of America.
authors.forename: Edward M
authors.identifier: 0000-0001-5665-9195
authors.initials: EM
authors.lastname: Campell
authors.affiliation: Heinrich-Pette-Institut, Leibniz-Institut für Experimentelle Virologie, Hamburg, Germany.
authors.forename: Carola
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Heinrich-Pette-Institut, Leibniz-Institut für Experimentelle Virologie, Hamburg, Germany.
authors.forename: Rudolph
authors.initials: R
authors.lastname: Reimer
authors.affiliation: Heinrich-Pette-Institut, Leibniz-Institut für Experimentelle Virologie, Hamburg, Germany.
authors.forename: Kay
authors.identifier: 0000-0002-4788-2691
authors.initials: K
authors.lastname: Grünewald
authors.affiliation: Department of Microbiology and Immunology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, United States of America.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Wiethoff
authors.affiliation: MFP CNRS UMR 5234, Microbiologie Fondamentale et Pathogénicité, Université de Bordeaux, Bordeaux, France.
authors.forename: Harald
authors.identifier: 0000-0002-4764-1708
authors.initials: H
authors.lastname: Wodrich
mesh_terms: D000256:Adenoviridae; D000258:Adenovirus Infections, Human / Q000276:immunology / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D015153:Blotting, Western; D036022:Capsid Proteins / Q000378:metabolism*; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D037161:Galectins / Q000378:metabolism*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D051379:Mice; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D053586:Virus Internalization
chemical_list: D036022:Capsid Proteins; D037161:Galectins; C091991:LGALS8 protein, human