title: Subversion of CtBP1-controlled macropinocytosis by human adenovirus serotype 3.
abstract: Endocytosis supports cell communication, growth, and pathogen infection. The species B human adenovirus serotype 3 (Ad3) is associated with epidemic conjunctivitis, and fatal respiratory and systemic disease. Here we show that Ad3 uses dynamin-independent endocytosis for rapid infectious entry into epithelial and haematopoietic cells. Unlike Ad5, which uses dynamin-dependent endocytosis, Ad3 endocytosis spatially and temporally coincided with enhanced fluid-phase uptake. It was sensitive to macropinocytosis inhibitors targeting F-actin, protein kinase C, the sodium-proton exchanger, and Rac1 but not Cdc42. Infectious Ad3 macropinocytosis required viral activation of p21-activated kinase 1 (PAK1) and the C-terminal binding protein 1 of E1A (CtBP1), recruited to macropinosomes. These macropinosomes also contained the Ad3 receptors CD46 and alpha v integrins. CtBP1 is a phosphorylation target of PAK1, and is bifunctionally involved in membrane traffic and transcriptional repression of cell cycle, cancer, and innate immunity pathways. Phosphorylation-defective S147A-CtBP1 blocked Ad3 but not Ad5 infection, providing a direct link between PAK1 and CtBP1. The data show that viruses induce macropinocytosis for infectious entry, a pathway used in antigen presentation and cell migration.
authors.affiliation: Institute of Zoology, University of Zürich, Zürich, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Amstutz
authors.forename: Michele
authors.initials: M
authors.lastname: Gastaldelli
authors.forename: Stefan
authors.initials: S
authors.lastname: Kälin
authors.forename: Nicola
authors.initials: N
authors.lastname: Imelli
authors.forename: Karin
authors.initials: K
authors.lastname: Boucke
authors.forename: Eliane
authors.initials: E
authors.lastname: Wandeler
authors.forename: Jason
authors.initials: J
authors.lastname: Mercer
authors.forename: Silvio
authors.initials: S
authors.lastname: Hemmi
authors.forename: Urs F
authors.initials: UF
authors.lastname: Greber
mesh_terms: D000199:Actins / Q000378:metabolism; D000257:Adenoviridae Infections / Q000821:virology; D000260:Adenoviruses, Human / Q000145:classification* / Q000378:metabolism* / Q000648:ultrastructure; D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D002966:Clathrin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D034281:Dynamins / Q000378:metabolism; D011992:Endosomes / Q000201:enzymology / Q000648:ultrastructure / Q000821:virology; D004789:Enzyme Activation; D006367:HeLa Cells; D006413:Hematopoietic System / Q000166:cytology / Q000821:virology; D006801:Humans; D016023:Integrins / Q000378:metabolism; D020014:K562 Cells; D008954:Models, Biological; D010873:Pinocytosis; D011493:Protein Kinase C / Q000378:metabolism; D012703:Serotyping; D053586:Virus Internalization; D054462:p21-Activated Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D002966:Clathrin; D004268:DNA-Binding Proteins; D016023:Integrins; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D054462:p21-Activated Kinases; D011493:Protein Kinase C; D020830:rac1 GTP-Binding Protein; D034281:Dynamins