A single link to the first track to allow the export script to build the search page
Erich Gulbins, University of Duisburg-Essen, Germany;
Although ceramides belong to the most hydrophobic molecules in a cell and are water insoluble, they are critically involved in many signalling pathways, in particular upon application of stress stimuli. Thus, activation of acid sphingomyelinase, which converts sphingomyelin to ceramide, is triggered by diverse receptors including those for CD95, TNF, IL-1, and PAF, and by cellular stress such as oxidative stress, chemotherapeutic agents or infection with bacterial and viral pathogens. We have introduced the concept that these stimuli trigger fusion of specialized secretory lysosomes with the plasma membrane, resulting in surface exposure of acid sphingomyelinase and generation of ceramide in the anti-cytoplasmic leaflet of cell membranes. Therein ceramide molecules spontaneously self associate to form small ceramide-enriched membrane domains that fuse to become large ceramide-enriched membrane platforms. These platforms serve to cluster cognate receptors and other signaling molecules to greatly amplify initial signal density, thereby mediating transmembrane effects of receptor activation or stress. Clustering of receptors seems to be mediated by the length and the aminoacid composition of the transmembrane domain. We applied these insights to cystic fibrosis and pulmonary infections with Pseudomonas aeruginosa. We have demonstrated that ceramide accumulates in tracheal and bronchial epithelial cells of cystic fibrosis mice and humans. In contrast, sphingosine is almost absent in these cells of cystic fibrosis mice and patients, while present in control mice and healthy individuals. Sphingosine very efficiently kills P. aeruginosa and prevents infection. Thus, cystic fibrosis mice and patients suffer from two defects of the sphingolipid metabolism, i.e. an increase of ceramide and a decrease of sphingosine that results in the marked sensitivity of cystic fibrosis animals and patients to develop P. aeruginosa infections. These insights may serve to develop novel strategies to prevent and treat pulmonary infections with Pseudomonas aeruginosa.