Caspase-dependent and -independent activation of acid sphingomyelinase signaling Journal Article


Authors: Rotolo, J. A.; Zhang, J.; Donepudi, M.; Lee, H.; Fuks, Z.; Kolesnick, R.
Article Title: Caspase-dependent and -independent activation of acid sphingomyelinase signaling
Abstract: Recent evidence suggests clustering of plasma membrane rafts into ceramide-enriched platforms serves as a transmembrane signaling mechanism for a subset of cell surface receptors and environmental stresses (Grassme, H., Jekle, A., Riehle, A., Schwarz, H., Berger, J., Sandhoff, K., Kolesnick, R., and Gulbins, E. (2001) J. Biol. Chem. 276, 20589-20596; Cremesti, A., Paris, F., Grassme, H., Holler, N., Tschopp, J., Fuks, Z., Gulbins, E., and Kolesnick, R. (2001) J. Biol. Chem. 276, 23954-23961). Translocation of the secretory form of acid sphingomyelinase (ASMase) into microscopic rafts generates therein the ceramide that drives raft coalescence. This process serves to feed forward Fas activation, with ∼2% of full caspase 8 activation sufficient for maximal ASMase translocation, leading to death-inducing signaling complex formation within ceramide-rich platforms, and apoptosis. Here we report that treatment of Jurkat T cells with UV-C also induces ASMase translocation into rafts within 1 min, catalyzing sphingomyelin hydrolysis to ceramide and raft clustering. In contrast to Fas, UV-induced ASMase translocation and activation were caspase-independent. Nonetheless, ceramide-rich platforms promoted UV-C-induced death signaling, because ASMase inhibition or raft disruption inhibited apoptosis, improving clonogenic cell survival. These studies thus define two distinct mechanisms for biologically relevant ASMase activation within rafts; a Fas-mediated mechanism dependent upon caspase 8 and FADD, and a UV-induced mechanism independent of caspase activation. Consistent with this notion, genetic depletion or pharmacologic inhibition of caspase 8 or FADD, which render Jurkat cells incapable of sphingolipid signaling and apoptosis upon Fas ligation, did not impair these events upon UV-C stimulation. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.
Keywords: signal transduction; controlled study; human cell; flow cytometry; ultraviolet radiation; t lymphocyte; plasmas; cell survival; apoptosis; enzyme inhibition; fas antigen; protein binding; intracellular transport; enzyme activation; dose-response relationship, drug; caspase; amino acid chloromethyl ketones; caspases; time factors; dose-response relationship, radiation; blotting, western; genetic engineering; cell membrane; protein transport; caspase 8; sphingolipids; ultraviolet rays; cell separation; hydrolysis; leukemia cell line; jurkat cells; ceramide; ceramides; sphingomyelin phosphodiesterase; sphingomyelin; cells; membranes; lipid raft; membrane microdomains; fas associated death domain protein; diacylglycerol kinase; arabidopsis proteins; transmembrane; ultraviolet c radiation; coalescence; plasma membrane rats; fatty acid desaturases
Journal Title: Journal of Biological Chemistry
Volume: 280
Issue: 28
ISSN: 0021-9258
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 2005-07-15
Start Page: 26425
End Page: 26434
Language: English
DOI: 10.1074/jbc.M414569200
PUBMED: 15849201
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 88" - "Export Date: 24 October 2012" - "CODEN: JBCHA" - "Source: Scopus"
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Citation Impact
MSK Authors
  1. Zvi Fuks
    396 Fuks
  2. Jianjun Zhang
    8 Zhang
  3. Richard N Kolesnick
    265 Kolesnick
  4. Jimmy A Rotolo
    33 Rotolo
  5. Hyunmi Lee
    9 Lee