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Caspase-8 and c-FLIPL associate in lipid rafts with NF-kappaB adaptors during T cell activation.
Journal of Biological Chemistry
Humans and mice lacking functional caspase-8 in T cells manifest a profound immunodeficiency syndrome due to defective T cell antigen receptor (TCR)-induced NF-kappaB signaling and proliferation. It is unknown how caspase-8 is activated following T cell stimulation, and what is the caspase-8 substrate(s) that is necessary to initiate T cell cycling. We observe that following TCR ligation, a small portion of total cellular caspase-8 and c-FLIP(L) rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIP(L) at a known caspase-8 cleavage site. The active caspase.c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-kappaB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-kappaB regulators PKC theta, CARMA1, Bcl-10, and MALT1, which connect to the TCR. The lack of caspase-8 results in the absence of MALT1 and Bcl-10 in the active caspase complex. Consistent with this observation, inhibition of caspase activity attenuates NF-kappaB activation. The current findings define a link among TCR, caspases, and the NF-kappaB pathway that occurs in a sequestered lipid raft environment in T cells.
Adaptor Proteins, Signal Transducing/metabolism, Alstrom Syndrome, Animals, Antigens, CD95/metabolism, Apoptosis Regulatory Proteins/metabolism, CARD Signaling Adaptor Proteins/metabolism, CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism, Caspase 8/metabolism, Caspases/metabolism, Enzyme Activation/physiology, GTPase-Activating Proteins/metabolism, Membrane Microdomains/genetics, Membrane Microdomains/metabolism, Mice, Mice, Knockout, Multiprotein Complexes/genetics, Multiprotein Complexes/metabolism, Neoplasm Proteins/metabolism, Protein Kinase C/metabolism, Receptors, Antigen, T-Cell/metabolism, Signal Transduction/physiology, T-Lymphocytes/cytology, T-Lymphocytes/metabolism, TNF Receptor-Associated Factor 2/metabolism, TNF Receptor-Associated Factor 6/metabolism
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