c-FLIP(S) reduces activation of caspase and NF-kappaB pathways and decreases T cell survival.
Effective stimulation of NF-kappaB in T cells following TCR ligation requires the activity of caspase-8. The active caspase-8 complex includes the paracaspase, MALT1, and Bcl-10, which connect to the NF-kappaB pathway. It has been less clear what regulates the level of caspase-8 activity during T cell activation. A likely candidate is cellular FLIP (c-FLIP), an enzymatically inert caspase-8 homologue. Two alternatively spliced forms of c-FLIP exist, a long form (c-FLIP(L)) and a short-form (c-FLIP(S)). The latter lacks the C-terminal caspase-like domain. c-FLIP(L) can heterodimerize with and activate caspase-8 through an activation loop in the C terminus of c-FLIP(L). Here we show that, in contrast to c-FLIP(L), c-FLIP(S) inhibits activation of caspase-8 in T cells, and consequently reduces recruitment of MALT1 and Bcl-10 to the active caspase complex. This results in reduced activity of NF-kappaB. Consequently, T cells from c-FLIP(S)-transgenic mice undergo more rapid cell death both spontaneously and after activation. The findings suggest that c-FLIP(S) functions to reduce the expansion of T cells during an immune response.
Hinshaw-Makepeace
Jennifer
J
Immunobiology Program, Department of Medicine, The University of Vermont College of Medicine, Burlington, VT 05405-0068, USA.
Huston
Gail
G
Fortner
Karen A
KA
Russell
Jennifer Q
JQ
Holoch
Daniel
D
Swain
Susan
S
Budd
Ralph C
RC
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D002470:Cell Survival; D004591:Electrophoresis, Polyacrylamide Gel; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000502:physiology*; D005434:Flow Cytometry; D020287:In Situ Nick-End Labeling; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D016328:NF-kappa B; D053148:Caspase 3; D053181:Caspase 8