Cutting edge: two distinct motifs within the Fas ligand tail regulate Fas ligand-mediated costimulation.
The cytoplasmic domain of Fas ligand is sufficient to costimulate CD8(+) T cells by driving Fas ligand recruitment into lipid rafts and association with select Src homology 3-containing proteins, activating PI3K and MAPK pathways, mediating nuclear translocation of the transcription factors NFAT and AP-1, and enhancing IFN-gamma production and Ag-specific CD8(+) T cell proliferation. We now show that Fas ligand molecules lacking amino acids 45-54 in the proline-rich region of the cytoplasmic domain fail to costimulate but serve as effective death inducers. Death induction and costimulation by Fas ligand are therefore clearly separable functions. Further, upon Fas ligand-mediated costimulation, casein kinase I phosphorylates Fas ligand, in which two conserved casein kinase I binding sites regulate NFAT activation and costimulation. These results help resolve how one molecule can serve as a double-edged immunomodulator by directing discrete biological consequences.
Sun
Mingyi
M
Department of Immunology, University of Washington, Seattle, WA 98195, USA.
Lee
Shinhee
S
Karray
Saoussen
S
Levi-Strauss
Matthieu
M
Ames
Kristina T
KT
Fink
Pamela J
PJ
D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D047389:Casein Kinase I / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004789:Enzyme Activation; D053222:Fas Ligand Protein / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D017353:Gene Deletion; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
D053222:Fas Ligand Protein; D050778:NFATC Transcription Factors; D047389:Casein Kinase I; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3