Listeriolysin O Causes ENaC Dysfunction in Human Airway Epithelial Cells
AbstractPulmonary permeability edema is characterized by reduced alveolar Na+ uptake capacity and capillary barrier dysfunction and is a potentially lethal complication of listeriosis. Apical Na+ uptake is mainly mediated by the epithelial sodium channel (ENaC) and initiates alveolar liquid clearance. Here we examine how listeriolysin O (LLO), the pore-forming toxin of Listeria monocytogenes, impairs the expression and activity of ENaC. To that purpose, we studied how sub-lytic concentrations of LLO affect negative and positive regulators of ENaC expression in the H441 airway epithelial cell line. LLO reduced expression of the crucial ENaC-α subunit in H441 cells within 2 h and this was preceded by activation of PKC-α, a negative regulator of the channel’s expression. At later time points, LLO caused a significant reduction in the phosphorylation of Sgk-1 at residue T256 and of Akt-1 at residue S473, both of which are required for full activation of ENaC. The TNF-derived TIP peptide prevented LLO-mediated PKC-α activation and restored phospho-Sgk-1-T256. The TIP peptide also counteracted the observed LLO-induced decrease in amiloride-sensitive Na+ current and ENaC-α expression in H441 cells. Intratracheally instilled LLO caused profound pulmonary edema formation in mice, an effect that was prevented by the TIP peptide; thus indicating the therapeutic potential of the peptide for the treatment of pore-forming toxin-associated permeability edema. View Full-Text
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Yang, G.; Pillich, H.; White, R.; Czikora, I.; Pochic, I.; Yue, Q.; Hudel, M.; Gorshkov, B.; Verin, A.; Sridhar, S.; Isales, C.M.; Eaton, D.C.; Hamacher, J.; Chakraborty, T.; Lucas, R. Listeriolysin O Causes ENaC Dysfunction in Human Airway Epithelial Cells. Toxins 2018, 10, 79.
Yang G, Pillich H, White R, Czikora I, Pochic I, Yue Q, Hudel M, Gorshkov B, Verin A, Sridhar S, Isales CM, Eaton DC, Hamacher J, Chakraborty T, Lucas R. Listeriolysin O Causes ENaC Dysfunction in Human Airway Epithelial Cells. Toxins. 2018; 10(2):79.Chicago/Turabian Style
Yang, Guang; Pillich, Helena; White, Richard; Czikora, Istvan; Pochic, Isabelle; Yue, Qiang; Hudel, Martina; Gorshkov, Boris; Verin, Alexander; Sridhar, Supriya; Isales, Carlos M.; Eaton, Douglas C.; Hamacher, Jürg; Chakraborty, Trinad; Lucas, Rudolf. 2018. "Listeriolysin O Causes ENaC Dysfunction in Human Airway Epithelial Cells." Toxins 10, no. 2: 79.
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