Caspase-8 and c-FLIPL associate in lipid rafts with NF-kappaB adaptors during T cell activation

J Biol Chem. 2007 Jul 6;282(27):19365-74. doi: 10.1074/jbc.M610610200. Epub 2007 Apr 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Alstrom Syndrome
  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • B-Cell CLL-Lymphoma 10 Protein
  • 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
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • 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
  • fas Receptor / metabolism


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • B-Cell CLL-Lymphoma 10 Protein
  • Bcl10 protein, mouse
  • CARD Signaling Adaptor Proteins
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Card11 protein, mouse
  • Cflar protein, mouse
  • GTPase-Activating Proteins
  • Multiprotein Complexes
  • Neoplasm Proteins
  • Ralbp1 protein, mouse
  • Receptors, Antigen, T-Cell
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 6
  • fas Receptor
  • Protein Kinase C
  • Caspase 8
  • Caspases
  • Malt1 protein, mouse
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein