title: Phospholipid scramblase 1 mediates type i interferon-induced protection against staphylococcal α-toxin.
abstract: The opportunistic gram-positive pathogen Staphylococcus aureus is a leading cause of pneumonia and sepsis. Staphylococcal α-toxin, a prototypical pore-forming toxin, is a major virulence factor of S. aureus clinical isolates, and lung epithelial cells are highly sensitive to α-toxin's cytolytic activity. Type I interferon (IFN) signaling activated in response to S. aureus increases pulmonary cell resistance to α-toxin, but the underlying mechanisms are uncharacterized. We show that IFNα protects human lung epithelial cells from α-toxin-induced intracellular ATP depletion and cell death by reducing extracellular ATP leakage. This effect depends on protein palmitoylation and induction of phospholipid scramblase 1 (PLSCR1). IFNα-induced PLSCR1 associates with the cytoskeleton after exposure to α-toxin, and cellular depletion of PLSCR1 negates IFN-induced protection from α-toxin. PLSCR1-deficient mice display enhanced sensitivity to inhaled α-toxin and an α-toxin-producing S. aureus strain. These results uncover PLSCR1 activity as part of an innate protective mechanism to a bacterial pore-forming toxin.
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Lizak
authors.forename: Timur O
authors.initials: TO
authors.lastname: Yarovinsky
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D001831:Body Temperature; D001835:Body Weight; D002460:Cell Line; D002470:Cell Survival; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology / Q000382:microbiology; D006460:Hemolysin Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology*; D054878:Lipoylation; D051379:Mice; D018345:Mice, Knockout; D049294:Phospholipid Transfer Proteins / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D013203:Staphylococcal Infections / Q000401:mortality / Q000473:pathology; D013211:Staphylococcus aureus / Q000276:immunology* / Q000472:pathogenicity*; D016019:Survival Analysis
chemical_list: D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D016898:Interferon-alpha; C493422:PLSCR1 protein, human; D049294:Phospholipid Transfer Proteins; C021091:staphylococcal alpha-toxin; D000255:Adenosine Triphosphate