Journal
CELL HOST & MICROBE
Volume 11, Issue 1, Pages 70-80Publisher
CELL PRESS
DOI: 10.1016/j.chom.2011.12.004
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Funding
- National Institutes of Health [5R21AI79322]
- Yale Liver Center [DK P30-34989]
- University of Iowa
- Yale University School of Medicine
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The opportunistic gram-positive pathogen Staphylococcus aureus is a leading cause of pneumonia and sepsis. Staphylococcal alpha-toxin, a prototypical pore-forming toxin, is a major virulence factor of S. aureus clinical isolates, and lung epithelial cells are highly sensitive to alpha-toxin's cytolytic activity. Type I interferon (IFN) signaling activated in response to S. aureus increases pulmonary cell resistance to alpha-toxin, but the underlying mechanisms are uncharacterized. We show that IFN alpha protects human lung epithelial cells from alpha-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). IFN alpha-induced PLSCR1 associates with the cytoskeleton after exposure to alpha-toxin, and cellular depletion of PLSCR1 negates IFN-induced protection from alpha-toxin. PLSCR1-deficient mice display enhanced sensitivity to inhaled alpha-toxin and an alpha-toxin-producing S. aureus strain. These results uncover PLSCR1 activity as part of an innate protective mechanism to a bacterial pore-forming toxin.
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