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

Oncogene. 2006 Sep 14;25(41):5612-25. doi: 10.1038/sj.onc.1209568. Epub 2006 Apr 24.


We have previously shown that activation of the acid sphingomyelinase (ASM), the release of ceramide and the formation of ceramide-enriched membrane domains are central for the induction of apoptosis by CD95. Here, we demonstrate that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD95 activate the ASM via a redox mechanism resulting in release of ceramide and formation of ceramide-enriched membrane platforms. Ceramide-enriched membrane platforms serve to cluster DR5 upon stimulation. Antioxidants prevent TRAIL-mediated stimulation of ASM, the release of ceramide, the formation of ceramide-enriched membrane platforms and the induction of apoptosis by TRAIL. Further, ASM-deficient splenocytes fail to cluster DR5 in ceramide-enriched membrane domains upon TRAIL stimulation and resist TRAIL-induced apoptosis, events that were restored by addition of natural C(16)-ceramide. A dose-response analysis indicates that ceramide-enriched membrane platforms greatly sensitized tumor cells to TRAIL-induced apoptosis. Our data indicate that ceramide-enriched membrane platforms are required for the signaling of TRAIL-DR5 complexes under physiological conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / physiology*
  • Cell Line
  • Ceramides / metabolism*
  • Enzyme Activation
  • Humans
  • Immunohistochemistry
  • Membrane Glycoproteins / physiology*
  • Mice
  • Oxidation-Reduction
  • Sphingomyelin Phosphodiesterase / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / physiology*


  • Apoptosis Regulatory Proteins
  • Ceramides
  • Membrane Glycoproteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Sphingomyelin Phosphodiesterase