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J. Biol. Chem., Vol. 280, Issue 28, 26425-26434, July 15, 2005

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Caspase-dependent and -independent Activation of Acid Sphingomyelinase Signaling^*

Jimmy A. Rotolo, Jianjun Zhang, Manjula Donepudi, Hyunmi Lee, Zvi Fuks¶, and Richard Kolesnick||

From the Laboratory of Signal Transduction and ^¶Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 and the Department of Pharmacology, Joan and Sanford I. Weill Graduate School of Medical Sciences, Cornell University, New York, New York 10021

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.

Received for publication, December 27, 2004 , and in revised form, April 6, 2005.

^* This work was supported by National Institutes of Health Grants CA85704 (to R. K.) and CA52462 (to Z. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Tel.: 212-639-7558; Fax: 212-794-4342; E-mail: r-kolesnick{at}ski.mskcc.org.

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