TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

Dumitru, Claudia A.; Gulbins, Erich

doi:10.1038/sj.onc.1209568

Cited by 153 publications

(135 citation statements)

References 67 publications

(81 reference statements)

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“…Ceramide molecules self-associate to small ceramide-enriched membrane microdomains, which have the tendency to spontaneously fuse to large ceramide-enriched membrane domains [36-38]. The formation of ceramide-enriched membrane domains was shown to occur in cells after stimulation via a variety of stimuli including CD95 [39-41], CD40 [42], DR5 [43], FcγRII [44], the PAF-receptor [45], but also after infection with P. aeruginosa [19], Neisseriae gonorrhoeae [46] , Rhinovirus [47], application of stress stimuli such as UV-light [48], cisplatin [49] or Cu 2+ -treatment [50]. The great variety of stimuli that trigger the formation of ceramide-enriched membrane platforms suggests that these membrane domains facilitate signal transduction, but are very likely not part of the specific signal transduction pathway elicited by the these stimuli.…”

Section: Ceramidementioning

confidence: 99%

“…However, further details of the stimulation of neutral sphingomyelinase are presently not known. The acid sphingomyelinase is activated by oxidation [43, 50, 72]. It is unknown whether the protein is directly oxidized in vivo or regulated via pathways that are redox-sensitive.…”

Section: Sphingomyelinasesmentioning

confidence: 99%

“…It is unknown whether the protein is directly oxidized in vivo or regulated via pathways that are redox-sensitive. Scavengers of reactive oxygen intermediates prevent activation of the acid sphingomyelinase by stimuli such as DR5 or Cu 2+ [43, 50, 72]. In vitro studies by Qui et al .…”

Section: Sphingomyelinasesmentioning

confidence: 99%

“…Other receptors, for instance CD95 or DR5, or infections with P. aeruginosa trigger a translocation of the acid sphingomyelinase onto the extracellular leaflet [39, 40, 43]. Translocation of the enzyme onto the outer leaflet of the cell membrane is very likely mediated by the fusion of vesicles, in particular secretory lysosomes that contain the enzyme [76], with the plasma membrane.…”

Section: Sphingomyelinasesmentioning

confidence: 99%

“…Ceramide has been demonstrated to mediate apoptosis by CD95 and DR5. Ceramide also activates cathepsin D in lysosomes to initiate the mitochondrial death pathway upon TNF-receptor activation [39, 43, 53]. However, at present it is unknown whether any death receptors or cathepsin D are involved in cell death observed in the airways of Cftr -deficient mice.…”

Section: Ceramide In Cystic Fibrosismentioning

confidence: 99%

See 4 more Smart Citations

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

Becker

Riethmüller²,

Zhang³

et al. 2010

TORMJ

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Sphingolipids and in particular ceramide have been shown to be critically involved in the response to many receptor-mediated, but also receptor-independent, mainly stress stimuli. Recent studies demonstrate that ceramide plays an important role in the pathogenesis of cystic fibrosis, a hereditary metabolic disorder caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator. Patients with cystic fibrosis suffer from chronic pulmonary inflammation and microbial lung infections, in particular with Pseudomonas aeruginosa. Chronic pulmonary inflammation in these patients seems to be the initial pathophysiological event. Inflammation may finally result in the high infection susceptibility of these patients, fibrosis and loss of lung function. Recent studies demonstrated that ceramide accumulates in lungs of cystic fibrosis mice and causes age-dependent pulmonary inflammation as indicated by accumulation of neutrophils and macrophages in the lung and increased pulmonary concentrations of Interleukins 1 and 8, death of bronchial epithelial cells, deposition of DNA in bronchi and high susceptibility to Pseudomonas aeruginosa infections. Genetic or pharmacological inhibition of the acid sphingomyelinase blocks excessive ceramide production in lungs of cystic fibrosis mice and corrects pathological lung findings. First clinical studies confirm that inhibition of the acid sphingomyelinase with small molecules might be a novel strategy to treat patients with cystic fibrosis.

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Section: Ceramidementioning

confidence: 99%

Section: Sphingomyelinasesmentioning

confidence: 99%

Section: Sphingomyelinasesmentioning

confidence: 99%

Section: Sphingomyelinasesmentioning

confidence: 99%

Section: Ceramide In Cystic Fibrosismentioning

confidence: 99%

See 3 more Smart Citations

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

Becker

Riethmüller²,

Zhang³

et al. 2010

TORMJ

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Lysosome and Cancer

Jäättelä

Kallunki

2016

Lysosomes: Biology, Diseases, and Therapeutics

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Ceramide in Pseudomonas aeruginosa infections

Riethmüller

Riehle

Grassmé

et al. 2007

Euro J Lipid Sci & Tech

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Ceramide in Pseudomonas aeruginosa infectionsCystic fibrosis (CF), the most common autosomal recessive disorder, at least in western countries, is caused by mutations of the cystic fibrosis transmembranous conductance regulator (CFTR) molecule and affects approximately 80,000 patients in Europe and the USA. Most, if not all, CF patients develop a chronic pulmonary infection with Pseudomonas aeruginosa. At present it is unknown why CF patients are highly sensitive to P. aeruginosa infections, and most importantly, no curative treatment for CF is available. P. aeruginosa infection results in an activation of the enzyme acid sphingomyelinase which catalyzes the release of ceramide from sphingomyelin in the cell membrane. Ceramide forms large ceramide-enriched membrane domains that are required for internalization of bacteria, induction of cell death in infected cells and a controlled release of cytokines from infected cells. Ceramide-enriched membrane platforms seem to serve the reorganization of receptors and intracellular signaling molecules involved in the infection of mammalian cells with P. aeruginosa. The significance of the acid sphingomyelinase and ceramide for the infection of mammalian cells with P. aeruginosa was demonstrated on mice genetically deficient for the acid sphingomyelinase. Further studies with N. gonorrhoeae, S. aureus and rhinoviruses indicate that ceramide-enriched membrane domains are also important for the infection of mammalian cells with other bacterial and viral pathogens, suggesting a general role of these membrane domains in infectious biology.

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TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

Cited by 153 publications

References 67 publications

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

Lysosome and Cancer

Ceramide in Pseudomonas aeruginosa infections

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