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Molecular and Cellular Biology, March 2006, p. 2118-2129, Vol. 26, No. 6
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.6.2118-2129.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

p38 Mitogen-Activated Protein Kinase Mediates the Fas-Induced Mitochondrial Death Pathway in CD8+ T Cells{dagger}

Nicholas Farley, Gustavo Pedraza-Alva, Diego Serrano-Gomez, Viswas Nagaleekar, Alexander Aronshtam, Troy Krahl, Tina Thornton, and Mercedes Rincón*

Immunobiology Program, Department of Medicine, University of Vermont, Burlington, Vermont 05405

Received 21 December 2005/ Accepted 22 December 2005

The p38 mitogen-activated protein kinase (MAPK) signaling pathway can be activated by a variety of stress stimuli such as UV radiation and osmotic stress. The regulation and role of this pathway in death receptor-induced apoptosis remain unclear and may depend on the specific death receptor and cell type. Here we show that binding of Fas ligand to Fas activates p38 MAPK in CD8+ T cells and that activation of this pathway is required for Fas-mediated CD8+ T-cell death. Active p38 MAPK phosphorylates Bcl-xL and Bcl-2 and prevents the accumulation of these antiapoptotic molecules within the mitochondria. Consequently, a loss of mitochondrial membrane potential and the release of cytochrome c lead to the activation of caspase 9 and, subsequently, caspase 3. Therefore, the activation of p38 MAPK is a critical link between Fas and the mitochondrial death pathway and is required for the Fas-induced apoptosis of CD8+ T cells.

* Corresponding author. Mailing address: Department of Medicine/Immunobiology Program, Given Medical Building D305, University of Vermont, Burlington, VT 05405. Phone: (802) 656-0937. Fax: (802) 656-3854. E-mail: mrincon{at}uvm.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, March 2006, p. 2118-2129, Vol. 26, No. 6
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.6.2118-2129.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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