The murine TRAIL receptor signals caspase-independent cell death through ceramide.
Death receptors such as the 55 kDa tumor necrosis factor (TNF) receptor (TNF-R55) or Fas can initiate both apoptotic (caspase-dependent) and caspase-independent routes to programmed cell death (PCD). Here, we demonstrate for the first time that the single murine receptor for (TNF)-related apoptosis-inducing ligand (mTRAIL-R2) can induce a caspase-independent form of PCD with necrosis-like features in addition to apoptosis. Analysis of morphological and cellular features of caspase-independent PCD in response to TRAIL and TNF suggests that mTRAIL-R2 and TNF-R55 elicit caspase-independent PCD through similar pathways, although without participation of cathepsins. Cells overexpressing acid ceramidase (AC), an enzyme that metabolizes the sphingolipid ceramide, show enhanced survival from TRAIL-induced caspase-independent PCD but not from apoptosis, implicating a function of ceramide as a key mediator in caspase-independent PCD (but not apoptosis) induced by mTRAIL-R2. In concert with the enhanced resistance of AC-overexpressing cells against caspase-independent PCD induced by TNF, our results suggest that ceramide acts as a common mediator of caspase-independent PCD caused by death receptors such as mTRAIL-R2 and TNF-R55.
Thon
Lutz
L
Institut für Immunologie, Universitätsklinikum Schleswig-Holstein Campus Kiel, Michaelisstr. 5, 24105 Kiel, Germany.
Mathieu
Sabine
S
Kabelitz
Dieter
D
Adam
Dieter
D
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D002518:Ceramides / Q000378:metabolism*; D002517:Galactosylgalactosylglucosylceramidase / Q000378:metabolism; D006801:Humans; D051379:Mice; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D053319:Tumor Necrosis Factor Decoy Receptors / Q000378:metabolism
D002518:Ceramides; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D053319:Tumor Necrosis Factor Decoy Receptors; C069521:recombinant human tumor necrosis factor-binding protein-1; D002517:Galactosylgalactosylglucosylceramidase; D020169:Caspases