Cellular FLIP long form augments caspase activity and death of T cells through heterodimerization with and activation of caspase-8.
Caspase activity is required not only for the death of T cells, but also for their activation. A delicate balance of caspase activity is thus required during T cell activation at a level that will not drive cell death. How caspase activity is initiated and regulated during T cell activation is not known. One logical candidate for this process is cellular FLIP long form (c-FLIP(L)), because it can block caspase-8 recruitment after Fas (CD95) ligation as well as directly heterodimerize with and activate caspase-8. The current findings demonstrate that after T cell activation, caspase-8 and c-FLIP(L) associate in a complex enriched for active caspases. This occurs coincidently with the cleavage of two known caspase-8 substrates, c-FLIP(L) and receptor interacting protein 1. Caspase activity is higher in wild-type CD8(+) than CD4(+) effector T cells. Increased expression of c-FLIP(L) results in augmented caspase activity in resting and effector T cells to levels that provoke cell death, especially of the CD8 subset. c-FLIP(L) is thus not only an inhibitor of cell death by Fas, it can also act as a principal activator of caspases independently of Fas.
Immunobiology Program, Department of Medicine, University of Vermont College of Medicine, Burlington, VT 05405, USA.
Austin
A
Dohrman
Jennifer Q
JQ
Russell
Solange
S
Cuenin
Karen
K
Fortner
Jürg
J
Tschopp
Ralph C
RC
Budd
D000818:Animals; D001483:Base Sequence; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D053181:Caspase 8; D020169:Caspases / Q000737:chemistry* / Q000378:metabolism*; D016923:Cell Death; D049109:Cell Proliferation; D018076:DNA, Complementary / Q000235:genetics; D019281:Dimerization; D004789:Enzyme Activation; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D019014:fas Receptor; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases