A capsid-encoded PPxY-motif facilitates adenovirus entry
| Autor: | Baptist Jammart, Zsolt Ruzsics, Eric J. Kremer, Daniel Henaff, Sigrid Seelmeir, Harald Wodrich, Carolina Segura-Morales, Christopher M. Wiethoff, Olivier Coux |
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| Přispěvatelé: | Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Max Von Pettenkofer Institute (MVP), Ludwig-Maximilians-Universität München (LMU), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Loyola University Medical Center (LUMC), Microbiologie cellulaire et moléculaire et pathogénicité ( MCMP ), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique ( CNRS ), Institut de Recherche en Infectiologie de Montpellier ( IRIM ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Max Von Pettenkofer Institute ( MVP ), Ludwig-Maximilians-Universität München, Centre de recherches de biochimie macromoléculaire ( CRBM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -IFR122-Centre National de la Recherche Scientifique ( CNRS ), Loyola University Medical Center ( LUMC ), Automatic mesh generation and advanced methods ( Gamma3 ), Institut Charles Delaunay ( ICD ), Université de Technologie de Troyes ( UTT ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Technologie de Troyes ( UTT ) -Centre National de la Recherche Scientifique ( CNRS ) -Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
MESH: Osteosarcoma
Nedd4 Ubiquitin Protein Ligases MESH : Capsid Proteins MESH: Microtubule-Organizing Center NEDD4 Retinal Pigment Epithelium Microtubules MESH : Ubiquitination Conserved sequence MESH: Endosomal Sorting Complexes Required for Transport Adenovirus Infections Human MESH: Protein Structure Tertiary Ubiquitin [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology Biology (General) Internalization Virology/Virion Structure Assembly and Egress Lung Conserved Sequence MESH : Microtubules MESH: Capsid Proteins media_common MESH : Adenoviruses Human 0303 health sciences Osteosarcoma MESH : Osteosarcoma MESH: Conserved Sequence MESH: Microtubules 030302 biochemistry & molecular biology MESH : Adenovirus Infections Human MESH: Retinal Pigment Epithelium 3. Good health Cell biology MESH : Epithelial Cells MESH : Microtubule-Organizing Center MESH: Adenovirus Infections Human [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology Capsid MESH : Retinal Pigment Epithelium MESH: Epithelial Cells MESH : Protein Structure Tertiary Research Article MESH: Adenoviruses Human MESH: Cell Line Tumor Endosome QH301-705.5 media_common.quotation_subject Ubiquitin-Protein Ligases MESH : Lung Immunology Endosomes Biology Microbiology 03 medical and health sciences Viral entry MESH : Conserved Sequence Virology Cell Line Tumor Genetics Humans MESH: Lung Molecular Biology 030304 developmental biology MESH: Humans Endosomal Sorting Complexes Required for Transport MESH : Cell Line Tumor Adenoviruses Human MESH : Humans Ubiquitination Epithelial Cells RC581-607 Virology/Host Invasion and Cell Entry MESH: Ubiquitin-Protein Ligases Protein Structure Tertiary MESH: Endosomes biology.protein MESH : Endosomal Sorting Complexes Required for Transport MESH : Endosomes MESH: Ubiquitination Parasitology Capsid Proteins MESH : Ubiquitin-Protein Ligases Immunologic diseases. Allergy Microtubule-Organizing Center |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Public Library of Science, 2010, 6 (3), pp.e1000808. ⟨10.1371/journal.ppat.1000808⟩ PLoS Pathogens, Public Library of Science, 2010, 6 (3), pp.e1000808. 〈10.1371/journal.ppat.1000808〉 PLoS Pathogens, Vol 6, Iss 3, p e1000808 (2010) |
| ISSN: | 1553-7366 1553-7374 |
| DOI: | 10.1371/journal.ppat.1000808⟩ |
| Popis: | 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. Author Summary Viruses exploit cellular functions during entry and exit of cells. To redirect cellular functions for their own purpose, viruses encode high-affinity binding sites for key-cellular factors. One such domain is the PPxY motif, which is present in structural proteins of several, mainly enveloped viruses. This motif binds to ubiquitin ligases of the Nedd4 family and recruits their function to sites of virus budding from cells. Here we show that adenoviruses also encode a PPxY motif in the internal structural protein VI and that the PPxY motif has an unprecedented function in virus entry. Adenoviruses with mutations in the protein VI PPxY motif undergo normal endosomal uptake and membrane penetration but have reduced infectivity, altered intracellular targeting and lack efficient gene-delivery. We also find that protein VI is ubiquitylated by Nedd4 ligases in a PPxY dependent manner following partial capsid disassembly and displays rapid intracellular movement. Depletion of Nedd4 ligases also alters virus movement within cells during entry and reduces viral infectivity. Given that PPxY motifs are important for virus exit our findings might have uncovered an additional function for PPxY motifs in virus entry, potentially expanding the significance of PPxY motifs and functionally related domains for viral replication. |
| Databáze: | OpenAIRE |
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