title: Phosphatidylethanolamine critically supports internalization of cell-penetrating protein C inhibitor.
abstract: 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.
authors.affiliation: Vaskuläre Biologie und Hämostase, Institut für Klinische Chemie, 81377 Munich, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Baumgärtner
authors.forename: Margarethe
authors.initials: M
authors.lastname: Geiger
authors.forename: Susanne
authors.initials: S
authors.lastname: Zieseniss
authors.forename: Julia
authors.initials: J
authors.lastname: Malleier
authors.forename: James A
authors.initials: JA
authors.lastname: Huntington
authors.forename: Karin
authors.initials: K
authors.lastname: Hochrainer
authors.forename: Edith
authors.initials: E
authors.lastname: Bielek
authors.forename: Mechthild
authors.initials: M
authors.lastname: Stoeckelhuber
authors.forename: Kirsten
authors.initials: K
authors.lastname: Lauber
authors.forename: Dag
authors.initials: D
authors.lastname: Scherfeld
authors.forename: Petra
authors.initials: P
authors.lastname: Schwille
authors.forename: Katja
authors.initials: K
authors.lastname: Wäldele
authors.forename: Klaus
authors.initials: K
authors.lastname: Beyer
authors.forename: Bernd
authors.initials: B
authors.lastname: Engelmann
mesh_terms: D000818:Animals; D001665:Binding Sites; D001710:Biotin / Q000378:metabolism; D001792:Blood Platelets / Q000737:chemistry / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D006098:Granulocytes / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007457:Iodine Radioisotopes / Q000378:metabolism; D007962:Leukocytes / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D009154:Mutation; D010714:Phosphatidylethanolamines / Q000378:metabolism*; D015539:Platelet Activation / Q000187:drug effects; D011485:Protein Binding; D018046:Protein C Inhibitor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D013997:Time Factors
chemical_list: D007457:Iodine Radioisotopes; D010714:Phosphatidylethanolamines; D018046:Protein C Inhibitor; D011994:Recombinant Proteins; D001710:Biotin; D013917:Thrombin