Phosphatidylethanolamine critically supports internalization of cell-penetrating protein C inhibitor

Research output: Contribution to journalResearch articleContributedpeer-review


  • Petra Baumgärtner - , Ludwig Maximilian University of Munich, Ludwig Institute for Cancer Research (Author)
  • Margarethe Geiger - , Medical University of Vienna (Author)
  • Susanne Zieseniss - , Ludwig Maximilian University of Munich (Author)
  • Julia Malleier - , Medical University of Vienna (Author)
  • James A. Huntington - , University of Cambridge (Author)
  • Karin Hochrainer - , Medical University of Vienna (Author)
  • Edith Bielek - , Medical University of Vienna (Author)
  • Mechthild Stoeckelhuber - , Ludwig Maximilian University of Munich (Author)
  • Kirsten Lauber - , University of Tübingen (Author)
  • Dag Scherfeld - , Max Planck Institute for Biophysical Chemistry (Karl Friedrich Bonhoeffer Institute) (Author)
  • Petra Schwille - , Max Planck Institute for Biophysical Chemistry (Karl Friedrich Bonhoeffer Institute) (Author)
  • Katja Wäldele - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Klaus Beyer - , Ludwig Maximilian University of Munich (Author)
  • Bernd Engelmann - , Hospital of the Ludwig-Maximilians-University (LMU) Munich, Ludwig Maximilian University of Munich (Author)


Although their contribution remains unclear, lipids may facilitate noncanonical routes of protein internalization into cells such as those used by cell-penetrating proteins. We show that protein C inhibitor (PCI), a serine protease inhibitor (serpin), rapidly transverses the plasma membrane, which persists at low temperatures and enables its nuclear targeting in vitro and in vivo. Cell membrane translocation of PCI necessarily requires phosphatidylethanolamine (PE). In parallel, PCI acts as a lipid transferase for PE. The internalized serpin promotes phagocytosis of bacteria, thus suggesting a function in host defense. Membrane insertion of PCI depends on the conical shape of PE and is associated with the formation of restricted aqueous compartments within the membrane. Gain- and loss-of-function mutations indicate that the transmembrane passage of PCI requires a branched cavity between its helices H and D, which, according to docking studies, precisely accommodates PE. Our findings show that its specific shape enables cell surface PE to drive plasma membrane translocation of cell-penetrating PCI.


Original languageEnglish
Pages (from-to)793-804
Number of pages12
JournalJournal of Cell Biology
Issue number4
Publication statusPublished - 19 Nov 2007
Externally publishedYes

External IDs

PubMed 18025309


ASJC Scopus subject areas