Subversion of CtBP1-controlled macropinocytosis by human adenovirus serotype 3

EMBO J. 2008 Apr 9;27(7):956-69. doi: 10.1038/emboj.2008.38. Epub 2008 Mar 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Adenoviridae Infections / virology
  • Adenoviruses, Human / classification*
  • Adenoviruses, Human / metabolism*
  • Adenoviruses, Human / ultrastructure
  • Alcohol Oxidoreductases / metabolism*
  • Clathrin / metabolism
  • DNA-Binding Proteins / metabolism*
  • Dynamins / metabolism
  • Endosomes / enzymology
  • Endosomes / ultrastructure
  • Endosomes / virology
  • Enzyme Activation
  • HeLa Cells
  • Hematopoietic System / cytology
  • Hematopoietic System / virology
  • Humans
  • Integrins / metabolism
  • K562 Cells
  • Models, Biological
  • Pinocytosis*
  • Protein Kinase C / metabolism
  • Serotyping
  • Virus Internalization
  • p21-Activated Kinases / metabolism
  • rac1 GTP-Binding Protein / metabolism


  • Actins
  • Clathrin
  • DNA-Binding Proteins
  • Integrins
  • Alcohol Oxidoreductases
  • C-terminal binding protein
  • p21-Activated Kinases
  • Protein Kinase C
  • rac1 GTP-Binding Protein
  • Dynamins