Vaccinia virus strains use distinct forms of macropinocytosis for host-cell entry

Jason Mercer, Stephan Knébel, Florian I Schmidt, Josh Crouse, Christine Burkard, Ari Helenius

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

To enter host cells, vaccinia virus, a prototype poxvirus, can induce transient macropinocytosis followed by endocytic internalization and penetration through the limiting membrane of pinosomes by membrane fusion. Although mature virions (MVs) of the Western reserve (WR) strain do this in HeLa cells by activating transient plasma membrane blebbing, MVs from the International Health Department-J strain were found to induce rapid formation (and lengthening) of filopodia. When the signaling pathways underlying these responses were compared, differences were observed at the level of Rho GTPases. Key to the filopodial formation was the virus-induced activation of Cdc42, and for the blebbing response the activation of Rac1. In addition, unlike WR, International Health Department-J MVs did not rely on genistein-sensitive tyrosine kinase and PI(3)K activities. Only WR MVs had membrane fusion activity at low pH. Inhibitor profiling showed that MVs from both strains entered cells by macropinocytosis and that this was induced by virion-exposed phosphatidylserine. Both MVs relied on the activation of epidermal growth factor receptor, on serine/threonine kinases, protein kinase C, and p21-activated kinase 1. The results showed that different strains of the same virus can elicit dramatically different responses in host cells during entry, and that different macropinocytic mechanisms are possible in the same cell line through subtle differences in the activating ligand.
Original languageEnglish
Pages (from-to)9346-51
Number of pages6
JournalProceedings of the National Academy of Sciences (PNAS)
Volume107
Issue number20
DOIs
Publication statusPublished - 18 May 2010

Keywords / Materials (for Non-textual outputs)

  • Flow Cytometry
  • Green Fluorescent Proteins
  • Hydrogen-Ion Concentration
  • Pinocytosis
  • Pseudopodia
  • RNA, Small Interfering
  • Receptor, Epidermal Growth Factor
  • Signal Transduction
  • Species Specificity
  • Transfection
  • Vaccinia virus
  • Virus Internalization
  • rho GTP-Binding Proteins

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