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J. Biol. Chem., Vol. 280, Issue 31, 28439-28450, August 5, 2005

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Diacylglycerol Kinase Regulates the Secretion of Lethal Exosomes Bearing Fas Ligand during Activation-induced Cell Death of T Lymphocytes^*

Roberto Alonso, M. Carmen Rodríguez, Jose Pindado¶, Ernesto Merino||, Isabel Mérida||, and Manuel Izquierdo**

From the Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas-Universidad de Valladolid, Facultad de Medicina, Ramón y Cajal, 7, 47005 Valladolid and Instituto de Investigaciones Biomédicas "Alberto Sols" Facultad de Medicina, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier, 4, 28029 Madrid and the ^||Department of Immunology and Oncology, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas, Campus de Cantoblanco, 28049 Madrid, Spain

Fas ligand (FasL) mediates both apoptotic and inflammatory responses in the immune system. FasL function critically depends on the different forms of FasL; soluble Fas ligand lacking the transmembrane and cytoplasmic domains is a poor mediator of apoptosis, whereas full-length, membrane-associated FasL (mFasL) is pro-apoptotic. mFasL can be released from T lymphocytes, via the secretion of mFasL-bearing exosomes. mFasL in exosomes retains its activity in triggering Fas-dependent apoptosis, providing an alternative mechanism of cell death that does not necessarily imply cell-to-cell contact. Diacylglycerol kinase (DGK), a diacylglycerol (DAG)-consuming enzyme, is involved in the attenuation of DAG-derived responses initiated at the plasma membrane that lead to T lymphocyte activation. Here we studied the role of DGK on activation-induced cell death on a T cell line and primary T lymphoblasts. The inhibition of DGK increases the secretion of lethal exosomes bearing mFas ligand and subsequent apoptosis. On the contrary, the overactivation of the DGK pathway inhibits exosome secretion and subsequent apoptosis. DGK was found associated with the trans-Golgi network and late endosomal compartments. Our results support the hypothesis that the DGK effect on apoptosis occurs via the regulation of the release of lethal exosomes by the exocytic pathway, and point out that the spatial orchestration of the different pools of DAG (plasma membrane and Golgi membranes) by DGK is crucial for the control of cell activation and also for the regulation of the secretion of lethal exosomes, which in turn controls cell death.

Received for publication, January 31, 2005 , and in revised form, April 26, 2005.

^* This work was supported in part by grants from Ministerio de Ciencia y Tecnología/European Union, Plan Nacional de Investigación Científica, Desarrollo e Innovación, SAF2003-00886. 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.

The on-line version of this article (available at http://www.jbc.org) contains Figs. 3, 4, and 9.

Recipient of a fellowship from the Spanish Ministerio de Ciencia y Tecnología.

^¶ Recipient of a fellowship from Fundación Francisco Cobos.

^** To whom correspondence should be addressed. Tel.: 34-91-4973117; E-mail: mizquierdo{at}iib.uam.es.

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