c-FLIP protects T lymphocytes from apoptosis in the intrinsic pathway.
Apoptosis can be induced by either death receptors on the plasma membrane (extrinsic pathway) or the damage of the genome and/or cellular organelles (intrinsic pathway). Previous studies suggest that cellular caspase 8 (FLICE)-like inhibitory protein (c-FLIP) promotes cell survival in death receptor-induced apoptosis pathway in T lymphocytes. Independent of death receptor signaling, mitochondria sense apoptotic stimuli and mediate the activation of effector caspases. Whether c-FLIP regulates mitochondrion-dependent apoptotic signals remains unknown. In this study, c-FLIP gene was deleted in mature T lymphocytes in vitro, and the role of c-FLIP protein in intrinsic apoptosis pathway was studied. In resting T cells treated with the intrinsic apoptosis inducer, c-FLIP suppressed cytochrome c release from mitochondria. Bim-deletion rescued the enhanced apoptosis in c-FLIP-deficient T cells, whereas inhibition of caspase 8 did not. Different from activated T cells, there was no necroptosis or increase in reactive oxygen species in c-FLIP-deficient resting T cells. These data suggest that c-FLIP is a negative regulator of intrinsic apoptosis pathway in T lymphocytes.
Department of Immunology, Duke University Medical Center, Durham, NC 27710.
Ming-Xiao
MX
He
Department of Immunology, Duke University Medical Center, Durham, NC 27710 youwen.he@duke.edu.
You-Wen
YW
He
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D045304:Cytochromes c / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D019311:Staurosporine