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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

04/28/2007

Pubmed ID

17462996

Pubmed Central ID

PMC4521413

DOI

10.1074/jbc.M610610200

Scopus ID

2-s2.0-34547111577   61 Citations

Abstract

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 RC

Author

Demin Wang PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adaptor Proteins, Signal Transducing
Alstrom 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
jenkins-FCD Prod-469 c3fc8ab87196149f9b23743c01b947d47e7319e5