Caspase-8 and c-FLIPL Associate in Lipid Rafts with NF-κB Adaptors during T Cell Activation (2007)

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-κB 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-FLIPL 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-FLIPL 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-κB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-κB regulators PKCθ, 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-κB activation. The current findings define a link among TCR, caspases, and the NF-κB pathway that occurs in a sequestered lipid raft environment in T cells. 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-κB 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-FLIPL 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-FLIPL 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-κB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-κB regulators PKCθ, 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-κB activation. The current findings define a link among TCR, caspases, and the NF-κB pathway that occurs in a sequestered lipid raft environment in T cells. Activation of caspases has traditionally been associated with oligomerization of death receptors and induction of cell death (1Degterev A. Boyce M. Yuan J. Oncogene. 2003; 22: 8543-8567Crossref PubMed Scopus (998) Google Scholar). It has been determined more recently that caspase activity is also required for the induction of proliferation by primary naïve human and murine T cells (2Alam A. Cohen L.Y. Aouad S. Sekaly R.P. J. Exp. Med. 1999; 190: 1879-1890Crossref PubMed Scopus (360) Google Scholar, 3Kennedy N.J. Kataoka T. Tschopp J. Budd R.C. J. Exp. Med. 1999; 190: 1891-1896Crossref PubMed Scopus (435) Google Scholar, 4Misra R.S. Jelley-Gibbs D.M. Russell J.Q. Huston G. Swain S.L. Budd R.C. J. Immunol. 2005; 174: 3999-4009Crossref PubMed Scopus (39) Google Scholar). Inhibition of caspase activity by the pan-caspase blocker, Z-VAD-fmk, 4The abbreviations used are: Z, benzyloxycarbonyl; fmk, fluoromethyl ketone; c-FLIPL, c-FLIP-Long form; TCR, T cell antigen receptor; MBCD, methyl-β-cyclodextran; IL, interleukin; MALT1, mucosa-associated lymphoid tissue translocation protein 1; CARMA1, caspase-recruitment domain membrane-associated guanylate kinase protein 1; PBS, phosphate-buffered saline; TRAF, tumor necrosis factor receptor-associated factor; LAT, linker for activation of T cells. or the caspase-8-specific blocker, IETD-fmk, greatly reduced production of IL-2 and proliferation following TCR ligation (2Alam A. Cohen L.Y. Aouad S. Sekaly R.P. J. Exp. Med. 1999; 190: 1879-1890Crossref PubMed Scopus (360) Google Scholar, 3Kennedy N.J. Kataoka T. Tschopp J. Budd R.C. J. Exp. Med. 1999; 190: 1891-1896Crossref PubMed Scopus (435) Google Scholar). It was subsequently shown that a non-functional mutation in the caspase-8 gene in humans (5Chun H.J. Zheng L. Ahmad M. Wang J. Speirs C.K. Siegel R.M. Dale J.K. Puck J. Davis J. Hall C.G. Skoda-Smith S. Atkinson T.P. Straus S.E. Lenardo M.J. Nature. 2002; 419: 395-399Crossref PubMed Scopus (586) Google Scholar, 6Su H. Bidere N. Zheng L. Cubre A. Sakai K. Dale J. Salmena L. Hakem R. Straus S. Lenardo M. Science. 2005; 307: 1465-1468Crossref PubMed Scopus (368) Google Scholar) or the deletion of caspase-8 in murine T cells (7Salmena L. Lemmers B. Hakem A. Matysiak-Zablocki K. D.M. L. A. A. Hakem R. 2003; PubMed Scopus Google Scholar) in an immunodeficiency syndrome by production of IL-2 and of T cells. It how caspase activation was to T cell antigen receptor ligation, what the and substrate(s) of caspase and this required the of the death receptor Fas was how the activation of caspase-8 to induction of We recently that following T cell cleavage occurs of known caspase as c-FLIP-Long and RIP1, caspase-8 associated with cell was R.S. Jelley-Gibbs D.M. Russell J.Q. Huston G. Swain S.L. Budd R.C. J. Immunol. 2005; 174: 3999-4009Crossref PubMed Scopus (39) Google Scholar). that active caspase-8 sequestered in a T cells activation. We the of c-FLIPL as an of caspase-8 and an caspase-8 T cell activation. c-FLIPL is to caspase-8 in death a mutation in the caspase which M. M. M. K. M. K. Tschopp J. Nature. PubMed Scopus Google Scholar). ligation of c-FLIPL is with caspase-8 to the complex (1Degterev A. Boyce M. Yuan J. Oncogene. 2003; 22: 8543-8567Crossref PubMed Scopus (998) Google Scholar, M. M. M. K. M. K. Tschopp J. Nature. PubMed Scopus Google Scholar). c-FLIPL is to with and caspase-8 in of Fas A. S. J. 2002; PubMed Scopus Google Scholar, M. N. Tschopp J. J. 2002; PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). c-FLIPL, a caspase cleavage at that A. S. S. J. PubMed Scopus Google Scholar, J. J. 1999; PubMed Scopus Google Scholar). c-FLIPL an caspase-8 T cell activation. c-FLIPL also associates with and to activation of NF-κB T. Budd R.C. N. M. M. K. 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PubMed Google Scholar). the mice (7Salmena L. Lemmers B. Hakem A. Matysiak-Zablocki K. D.M. L. A. A. Hakem R. 2003; PubMed Scopus Google Scholar) and mice for MALT1 D.M. Science. 2003; PubMed Scopus Google Bcl-10 J. A. L. S. A. PubMed Scopus Google Scholar, J. A. 2003; PubMed Scopus Google or T. B. B. M.J. K. M. 2003; PubMed Scopus Google Scholar, B. B. S. Tschopp J. M. Immunol. 2002; PubMed Scopus Google Scholar, H. T. S. N. M. B. S. G. R. 2003; PubMed Scopus Google a link caspase-8 activation and the MALT1 complex. CARMA1, Bcl-10, and MALT1 to lipid rafts TCR stimulation, that the active caspase complex in activated T cells A. Kataoka T. S. Russell J.Q. Tschopp J. Budd R.C. J. Immunol. 2005; 174: PubMed Scopus Google Scholar) in lipid rafts and with CARMA1, Bcl-10, and the current that T cells manifest to of active this following activation of T cells in with lipid caspase-8 activation occurs rapidly and in the absence of Fas with cleavage of c-FLIPL to is the of the active caspase complex with of the NF-κB activation PKCθ, CARMA1, Bcl-10, MALT1, as well as RIP1, and the complex. findings the of caspase and how this to NF-κB mice c-FLIPL in the T cell Kataoka T. A. M. A. Budd R.C. Tschopp J. 2002; 22: PubMed Scopus Google NF-κB mice R.S. S. A. M. J. PubMed Scopus Google and T cell mice (7Salmena L. Lemmers B. Hakem A. Matysiak-Zablocki K. D.M. L. A. A. Hakem R. 2003; PubMed Scopus Google Scholar) and in the of and used at of The is and by the of of of and mice the mice J. A. L. S. A. PubMed Scopus Google Scholar) at The of and mice J. A. 2003; PubMed Scopus Google Scholar) at the of The mice the gene by of the M. S. PubMed Scopus Google Scholar). T and cells and in with of was T cells by with and for and with and at a of to cell at for was used to cells. and in and T and T cells activated in by and human IL-2 for and with activation T cells with with for or T cells activated with and of T cells mice with PBS, and The and in a for for as the with of with and with in at for at portion of the cells was at to as a for and the cells cells in and was determined by for in and or and in at for at in of the following primary Bcl-10 caspase-8 of The and Hall of and MALT1 a and and with and with to among the of and cells in human IL-2 with at for a a portion of T cells was with to with for in of or of and lipid raft by with of at for with of and at in in by and was and T cells in PBS, in with and for Siegel R.M. Immunol. PubMed Scopus Google Scholar). for and for with to a of was to or by with The was in an and the and the at at with the portion of was used for active caspase and portion was used for caspase determined the or T cells in at in and with of caspase to the a of The shown at for and for and T cells with in and and for at with at a of for at with and lipid rafts cells activated with for and T cells with to in and in of T of total cellular caspase-8 and T and caspase-8 activation following TCR in cell death is necessary to initiate cell N.J. Kataoka T. Tschopp J. Budd R.C. J. Exp. Med. 1999; 190: 1891-1896Crossref PubMed Scopus (435) Google Scholar, 4Misra R.S. Jelley-Gibbs D.M. Russell J.Q. Huston G. Swain S.L. Budd R.C. J. Immunol. 2005; 174: 3999-4009Crossref PubMed Scopus (39) Google Scholar). of death caspase-8 activation in a sequestered signaling by TCR activation in lipid and lipid rafts the T cell J. K. PubMed Scopus Google the of caspase-8 and c-FLIPL to this with and with a followed by for and for a and the which in to lipid rafts in T cells N. M. M. J. Immunol. 2002; PubMed Scopus Google Scholar). and to lipid the of T cells that caspase-8 and c-FLIPL to the T cells a small of caspase-8 and c-FLIPL in the lipid raft that T cells manifest caspase activity A. Kataoka T. S. Russell J.Q. Tschopp J. Budd R.C. J. Immunol. 2005; 174: PubMed Scopus Google and that c-FLIPL with and caspase-8 M. N. Tschopp J. J. 2002; PubMed Scopus Google Scholar, A. Russell J.Q. S. K. Tschopp J. Budd R.C. J. Immunol. 2005; PubMed Scopus Google Scholar). to T T cells and T cells the lipid raft an of and caspase-8 and caspase-8 and c-FLIPL known caspase-8 cleavage in that caspase-8 and M. N. Tschopp J. J. 2002; PubMed Scopus Google Scholar). the of to caspase-8 and was in the lipid raft with the of T cells findings that active caspase-8 in the raft this more and T cells with to and raft and in lipid rafts and was with by and to active shown in active caspase-8 was in T cells in the raft or in T active caspase-8 and caspase-8 lipid raft the of caspase-8 in and c-FLIPL with the active caspase complex in lipid the of which was to the in the cell is with the that caspase activity was in the lipid raft c-FLIPL and caspase-8 migrate to lipid rafts following TCR ligation, and this the activation of caspase-8 and cleavage of NF-κB to and with A. Kataoka T. S. Russell J.Q. Tschopp J. Budd R.C. J. Immunol. 2005; 174: PubMed Scopus Google Scholar) and T. Tschopp J. PubMed Scopus Google Scholar) that associate with the and RIP1, to activation of pathway TCR to NF-κB activation has been more recently to PKCθ, CARMA1, MALT1, and Bcl-10 M. Immunol. 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Wang PubMed Scopus Google Scholar, 2005; PubMed Scopus Google as a of to forms of and in the lipid raft lipid rafts T cells of the for activation of with active of the NF-κB pathway with caspase-8 in lipid molecules associated with active T cells with and lipid raft and to with PKCθ, CARMA1, MALT1, Bcl-10, RIP1, TRAF2, TRAF6, and in active caspase lipid and in the the portion of in the linker for activation of T cells raft M. A. Immunol. 2003; PubMed Scopus Google Scholar, A. M. PubMed Scopus Google Scholar) was in the active caspase complex of the was by the of a of to for of to active caspases, and for the to molecules as MALT1 and Bcl-10 MALT1 is a shown that caspase activity and T. L. M. PubMed Scopus Google Scholar). of the active caspase complex was also of Fas as the in T cells active caspase-8 and NF-κB signaling in lipid rafts of T cells. for of MALT1 and Bcl-10 in the to active caspases, to what the of caspase-8 was required for the of MALT1 and used mice a deletion of caspase-8 in the T cell mice and with mice (7Salmena L. Lemmers B. Hakem A. Matysiak-Zablocki K. D.M. L. A. A. Hakem R. 2003; PubMed Scopus Google Scholar). T cells mice known to to TCR T cells mice or mice with with and for MALT1, and cell T cells of MALT1 and Bcl-10 as T cells of molecules was in the T cells Bcl-10 and MALT1 associate an domain MALT1 M. Immunol. PubMed Scopus Google the of of MALT1 and Bcl-10 to the active caspase complex the of the T cells and mice and caspases and for MALT1, and T cells and of total caspase-8 in cell as well as of active caspase-8 in and Bcl-10 and MALT1 associated with active caspases in T cells. T cells MALT1 associated with active caspases findings in a was with the of MALT1 to associate with Bcl-10 M. Immunol. PubMed Scopus Google Scholar, M. N. S. M. G. J. PubMed Scopus Google which was by of MALT1 with Bcl-10 T cells Bcl-10 in the active caspase complex Bcl-10 MALT1 to the active caspase complex in T cells. The following TCR how caspase-8 activation occurs TCR and how rapidly NF-κB signaling associate with active T cells or following with for or was with for an to caspases cell of protein and for MALT1, and T cells active this to the shown in activation or death of T cells or more the of proliferation of T cells in mice Budd R.C. J. Immunol. 2005; PubMed Scopus Google Scholar). caspase-8 activation rapidly of TCR The of associated MALT1 and Bcl-10 also rapidly with the of active that active caspase-8 rapidly with of the NF-κB signaling pathway following TCR The activation of caspase-8 was in the rapid of total caspase activity the of cell following TCR cells with the and for with and to IL-2 for an to cell cells of T cells. T cells the of cell and caspase activity was T cells of caspase with naïve T cells R.S. Jelley-Gibbs D.M. Russell J.Q. Huston G. Swain S.L. Budd R.C. J. Immunol. 2005; 174: 3999-4009Crossref PubMed Scopus (39) Google Scholar). of caspase activation cell and this with cell findings with the of an active caspase complex following T cell and with of an active caspase complex in T cells. caspase activity was necessary for activation of mice that the NF-κB to a R.S. S. A. M. J. PubMed Scopus Google Scholar, M. S. PubMed Scopus Google caspase with NF-κB activity in activated T cells The findings in of of the the active caspase-8 that rapidly forms in lipid rafts T cell activation is in T cells and associates with NF-κB signaling of lipid rafts the activation of T cells or with the for and lipid raft and of cell a the lipid raft of and in the of lipid raft to T cells or with for followed by TCR for a T cells or with for in the absence of TCR was with for an to active caspases, and of protein was used to active caspases and for MALT1, Bcl-10, and The a of active caspase-8 T cells with to TCR for as well as T cells with the of MALT1 and Bcl-10 with active caspases of lipid active was in T cells of TCR of that caspase-8 activation activation. T cells active with (2Alam A. Cohen L.Y. Aouad S. Sekaly R.P. J. Exp. Med. 1999; 190: 1879-1890Crossref PubMed Scopus (360) Google Scholar, 4Misra R.S. Jelley-Gibbs D.M. Russell J.Q. Huston G. Swain S.L. Budd R.C. J. Immunol. 2005; 174: 3999-4009Crossref PubMed Scopus (39) Google Scholar, Cohen L.Y. A. Sekaly R.P. J. Immunol. PubMed Scopus Google Scholar). is activated by the of active was by also as a that was to and active caspases in the of activation of caspase-8 is the of lipid The current findings that following T cell activation is rapid and activation of caspase-8 lipid and in with of c-FLIPL the of active caspase-8 in T cells the shown of c-FLIPL with caspase-8 M. N. Tschopp J. J. 2002; PubMed Scopus Google Scholar, A. Russell J.Q. S. K. Tschopp J. Budd R.C. J. Immunol. 2005; PubMed Scopus Google Scholar). c-FLIPL is at for caspase-8 in this The active caspase complex also associates with of the NF-κB signaling pathway of Fas that caspase activity in T cells is necessary for activation of NF-κB H. Bidere N. Zheng L. Cubre A. Sakai K. Dale J. Salmena L. Hakem R. Straus S. Lenardo M. Science. 2005; 307: 1465-1468Crossref PubMed Scopus (368) Google Scholar). results a in which caspase-8 activation occurs in a sequestered environment that the of caspase-8 activation as well as the cleavage of caspase-8 to with NF-κB activation and with cell The of c-FLIPL with active caspases a for c-FLIPL in the activation of is with that c-FLIPL an activation that with the of caspase-8 M. N. Tschopp J. J. 2002; PubMed Scopus Google Scholar). c-FLIPL is rapidly by caspase-8 to A. S. J. 2002; PubMed Scopus Google Scholar, A. S. S. J. PubMed Scopus Google Scholar, J. 1999; PubMed Scopus Google Scholar). of is T cell activation N.J. Kataoka T. Tschopp J. Budd R.C. J. Exp. Med. 1999; 190: 1891-1896Crossref PubMed Scopus (435) Google Scholar, 4Misra R.S. Jelley-Gibbs D.M. Russell J.Q. Huston G. Swain S.L. Budd R.C. J. Immunol. 2005; 174: 3999-4009Crossref PubMed Scopus (39) Google Scholar) and associates more with and c-FLIPL T. Budd R.C. N. M. M. K. M. N. M. Tschopp J. PubMed Scopus Google Scholar, A. Kataoka T. S. Russell J.Q. Tschopp J. Budd R.C. J. Immunol. 2005; 174: PubMed Scopus Google Scholar, T. Tschopp J. PubMed Scopus Google Scholar). Consistent with induction of NF-κB activity by c-FLIPL caspase NF-κB of caspase activity T. Tschopp J. PubMed Scopus Google Scholar). caspase cleavage of c-FLIPL of the has also been recently to with A. J. 2005; PubMed Scopus Google Scholar). findings at for the of caspase-8 activity in T cell caspase-8 as a for the that caspase-8 activation is necessary for T cell proliferation of humans an T cells to TCR and manifest activation of NF-κB (5Chun H.J. Zheng L. Ahmad M. Wang J. Speirs C.K. Siegel R.M. Dale J.K. Puck J. Davis J. Hall C.G. Skoda-Smith S. Atkinson T.P. Straus S.E. Lenardo M.J. Nature. 2002; 419: 395-399Crossref PubMed Scopus (586) Google Scholar, 6Su H. Bidere N. Zheng L. Cubre A. Sakai K. Dale J. Salmena L. Hakem R. Straus S. Lenardo M. 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