Caspase-8 and c-FLIPL associate in lipid rafts with NF-kappaB adaptors during T cell activation. J Biol Chem 2007 Jul 06;282(27):19365-74
Date
04/28/2007Pubmed ID
17462996Pubmed Central ID
PMC4521413DOI
10.1074/jbc.M610610200Scopus ID
2-s2.0-34547111577 (requires institutional sign-in at Scopus site) 64 CitationsAbstract
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.
Author List
Misra RS, Russell JQ, Koenig A, Hinshaw-Makepeace JA, Wen R, Wang D, Huo H, Littman DR, Ferch U, Ruland J, Thome M, Budd RCAuthor
Demin Wang PhD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAlstrom Syndrome
Animals
Apoptosis Regulatory Proteins
B-Cell CLL-Lymphoma 10 Protein
CARD Signaling Adaptor Proteins
CASP8 and FADD-Like Apoptosis Regulating Protein
Caspase 8
Caspases
Enzyme Activation
GTPase-Activating Proteins
Membrane Microdomains
Mice
Mice, Knockout
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
Multiprotein Complexes
Neoplasm Proteins
Protein Kinase C
Receptors, Antigen, T-Cell
Signal Transduction
T-Lymphocytes
TNF Receptor-Associated Factor 2
TNF Receptor-Associated Factor 6
fas Receptor