Subversion of CtBP1-controlled macropinocytosis by human adenovirus serotype 3

Authors:
Amstutz B, Gastaldelli M, Kälin S, Imelli N, Boucke K, Wandeler E, Mercer J, Hemmi S, Greber UF
In:
Source: EMBO J
Publication Date: (2008)
Issue: 27(7): 956-69
Research Area:
Cancer Research/Cell Biology
Immunotherapy / Hematology
Cells used in publication:
K-562
Species: human
Tissue Origin: blood
Platform:
Nucleofector™ I/II/2b
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 alphav 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.